5-(arylsulfonyl)-,5-(arylsulfinyl), and 5-(arylsulfanyl)-thiazolidine-2,4-diones useful for inhibition of farnesyl-protein transferase

ABSTRACT

This invention relates to a method of using novel 5-(arylsulfonyl)-,5-(arylsulfinyl), and 5-(arylsulfanyl)-thiazolidine-2,4-diones of Formula (I), wherein Ar, Ar′, R 6 , m and n are as defined in the specification as inhibitors of Ras FPTase, and may be used as an alternative to, or in conjunction with, traditional cancer therapy for treating ras-oncogene-dependent tumors, such as cancers of the pancreas, colon, bladder, and thyroid.

“This application claims priority from copending provisionalapplications Serial No. 60/314,586 and 60/314,621 filed on Aug. 24, 2001the entire disclosure of which are hereby incorporated by reference.”

FIELD OF THE INVENTION

This invention relates to a novel series of5-(arylsulfonyl)-,5-(arylsulfinyl), and5-(arylsulfanyl)-thiazolidine-2,4-diones of formula (I) to their use incancer therapy, to pharmaceutical compositions containing them, and to aprocess for their preparation. The compounds are inhibitors of RasFPTase, and may be used as an alternative to, or in conjunction with,traditional cancer therapy for treating ras- oncogene-dependent tumors,such as cancers of the pancreas, colon, bladder, and thyroid. Compoundsin the invention may also be useful for controlling metastasis,suppressing angiogenesis, inducing apoptosis, and in treatingRas-associated proliferative diseases other than cancer, such asrestenosis, neuro-fibromatosis, endometriosis, and psoriasis. Thesecompounds may also inhibit prenylation of proteins other than Ras, andthus be effective in the treatment of diseases associated with otherprenyl modifications of proteins.

BACKGROUND OF THE INVENTION

Mammalian H-, K-, and N-Ras proteins, encoded by H-, K-, and N-rasproto-oncogenes, respectively, are 21 kD GTP-binding proteins whichpossess intrinsic GTPase activity and play a fundamental role in cellproliferation and differentiation (G. L. Bolton, J. S. Sebolt-Leopold,and J. C. Hodges, Annu. Rep. Med. Chem., 1994, 29, 165; R. J. A. Grandin “New Molecular Targets in Cancer Chemotherapy” J. D. Kerr, and P.Workman, Eds., CRC Press, Boca Raton, Fla., 1994, p. 97). Specificmutations in the ras gene impair GTPase activity of Ras, leading touninterrupted growth signals and to the transformation of normal cellsinto malignant phenotypes. Mutant ras oncogenes are found inapproximately 25% of all human cancers, including 90% of pancreatic, 50%of colon, and 50% of thyroid tumors (J. L. Bos, Cancer Res., 1989, 49,4682). It has been shown that normal cells transfected with mutant rasgene become cancerous and that unfarnesylated, cytosolic mutant Rasprotein does not anchor in cell membranes and cannot induce thistransformation (J. F. Hancock, H. Paterson, and C. J. Marshall, Cell,1990, 63,133). Posttranslational modification and plasma membraneassociation of mutant Ras is essential for this transforming activity.The first and required step in the processing of Ras is farnesylation atthe cysteine residue of its carboxyl terminal motif, CAAX (C=Cys-186,A=aliphatic amino acid, X=usually methionine, serine or glutamine).Since its identification, the enzyme farnesyl-protein transferase(FPTase) that catalyzes this first processing step has emerged as apromising target for therapeutic intervention (H.-W. Park, S. R.Boduluri, J. F. Moomaw, P. J. Casey, and L. S. Beese, Science, 1997,275, 1800; P. J. Casey, P. A. Solski, C. J. Der, and J. E. Buss, Proc.Natl. Acad. Sci. U.S.A., 1989, 86, 8323; S. Ayral-Kaloustian and J. S.Skotnicki, Annu. Rep. Med. Chem., 1996, 31, 165, and referencestherein). Major milestones have been achieved with small molecules, suchas mimics of the tetrapeptide CAAX and analogs of farnesylpyrophosphate, that show efficacy without toxicity in vitro as well asin mouse models bearing ras-dependent tumors or human xenografts withH-, N-, or K-ras mutations (S. Ayral-Kaloustian and J. S. Skotnicki,Annu. Rep. Med. Chem., 1996, 31, 165, and references therein; T. M.Williams, Exp. Opin. Ther. Patents, 1998, 8, 553, and referencestherein). Several low-molecular weight compounds that inhibit FPTasehave entered Phase I trials in humans (SCH-66336, Pharmaprojects, 1998,No. 5128; R-115777, Pharmaprojects, 1998, No. 5532).

5-[3-aryl-prop-2-ynyl]-5-(arylsulfonyl)thiazolidine-2,4-diones and5-[3-aryl-prop-2-ynyl]-5-(arylsulfanyl)thiazolidine-2,4-diones whichpossess antihyperglycemic activity, are reported in U.S. Pat. Nos.5,574,051 and 5,605,918.

Accordingly, there is still a need for drugs for treating and preventingcancer. In particular, there is a need for drugs which inhibit or treatthe growth of tumors expressing an activated Ras oncogene and whichinclude cancers of the pancreas, colon, bladder and thyroid.

BRIEF SUMMARY OF THE INVENTION

The present invention disclosed compounds represented by Formula (I):

wherein:

Ar is 1-naphthyl, 2-naphthyl, 8-quinolinyl, 2-thienyl,5-chloro-2-thienyl, 5-(2-pyridyl)-2-thienyl, 2-pyridinyl, substituted2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl, 2-pyrimidinyl,2-benzoxazolyl, 2-benzthiazolyl, 2-benzimidazolyl, 2-furanyl,2-benzo-[b]-furanyl, 2-benzo-[b]-thienyl or a moiety of the formula:

R₁ is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms,4-pyridyloxy, azido, nitro,acetamido, trifluoromethoxy, phenoxy, or benzyloxy;

R₂ is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, trifluoromethoxy, phenoxy, orbenzyloxy;

m is 0, 1 or 2;

R₆ is hydrogen, alkyl of 1 to 6 carbon atoms, benzyl, substitutedbenzyl, imidazolylpropyl, or —CO₂Y;

Y is 2-methoxyethyl, alkyl is 1 to 6 carbon atoms, benzyl, orsubstituted benzyl;

W is

 E— and Z——CH═CH—, —CONH—, —CONHCH₂—, —CONHCH₂CH₂—, or —CH₂—CH₂—;

n is an integer of 1 to 9;

Ar′ is thienyl, pyridinyl or a moiety of the formula:

R₃, R₄, R₅, are independently selected from hydrogen, alkoxy of 1 to 6carbon atoms, alkyl of 1 to 6 carbon atoms, fluoro, bromo, chloro, iodo,nitro, amino, hydroxy, azido, cyano, phenyl, phenoxy, trifluoromethyl,trifluoromethoxy, methanesulphonyl, 1-pyrrolyl, —CO₂R₇, —CONHR₈,—CH₂CONHR₉, —NHCO₂R₁₀, —NHCOR₁₁, and —NHCONHR₁₂;

R₇ is selected from H, and alkyl of 1 to 6 carbon atoms,

R₈ is selected from H, and alkyl of 1 to 6 carbon atoms;

R₉ is selected from H, and alkyl of 1 to 6 carbon atoms;

R₁₀ is selected from alkyl of 1 to 6 carbon atoms, benzyl, nitrobenzyl,and chlorophenyl;

R₁₁ is selected from alkyl of 1 to 6 carbon atoms, benzyl, phenyl,halophenyl, alkyl(1 to 6 carbon atoms)phenyl, alkoxy(1 to 6 carbonatoms)phenyl, and biphenyl;

R₁₂ is benzyl, alkyl of 1 to 6 carbon atoms, alkoxy(1 to 6 carbonatoms)phenyl, halophenyl, and alkyl(1 to 6 carbon atoms)phenyl;

provided that when W is

 then n is other than 2;

further provided that when n is 1, m is 0 or 2, R₆ is H and W is

 then:

Ar is not phenyl, 2-naphthyl, alkyl substituted phenyl, alkoxysubstituted phenyl, halogen substituted phenyl, 2-pyridinyl, substituted2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl, 2-pyrimidinyl,2-benzoxazolyl, 2-benzthiazolyl, 2-benzimidazolyl, 2-furanyl,2-benzo-[b]-furanyl, 2-thienyl, 2-benzo-[b]-thienyl; and

Ar′ is not phenyl, alkyl substituted phenyl, perfluoroalkyl (mono ordi)substituted phenyl, halogen substituted phenyl, alkoxy substitutedphenyl, perfluoroalkoxy substituted phenyl and alkylthio substitutedphenyl;

or pharmaceutically acceptable salts thereof.

Among the preferred groups of compounds of Formula (I) of this inventionincluding pharmaceutically acceptable salts thereof are those in thesubgroups below, wherein the other variables of Formula (I) in thesubgroups are as defined above wherein:

a.) R₆ is hydrogen, n is 3, m is 2, W is

b.) R₆ is hydrogen, n is 3, m is 2, W is

 Ar is a moiety of the formula:

c.) R₆ is hydrogen, n is 3, m is 2, W is

 Ar is a moiety of the formula:

Ar′ is a moiety of the formula:

d.) R₆ is hydrogen, n is 3, m is 2, W is

 Ar is a moiety of the formula:

Ar′ is thienyl or pyridinyl;

e.) R₆ is hydrogen, n is 3-6, m is 2, W is

f.) R₆ is hydrogen, n is 3-6, m is 2, W is

 Ar is a moiety of the formula:

g.) R₆ is hydrogen, n is 3-6, m is 2, W is

 Ar is a moiety of the formula:

Ar′ is a moiety of the formula:

h.) R₆ is hydrogen, n is 3-6, m is 2, W is

 Ar is a moiety of the formula:

Ar′ is thienyl or pyridinyl;

i.) R₆ is hydrogen, n is 1, m is 2, W is

j.) R₆ is hydrogen, n is 1, m is 2, W is

 Ar is a moiety of the formula:

k.) R₆ is hydrogen, n is 1, m is 2, W is

 Ar is a moiety of the formula:

Ar′ is a moiety of the formula:

l.) R₆ is hydrogen, n is 1, m is 2, W is

 Ar is a moiety of the formula:

Ar′ is thienyl or pyridinyl;

Additionally preferred compounds of this invention include compounds ofFormula (I) in which m is 2, Ar is phenyl substituted in the 4-positionby iodo, methoxy, trifluoromethoxy, 4-pyridyloxy; Ar′ is phenylsubstituted in the 2-position by chloro or methyl, and in the 5-positionby amino, chloro, a carbamic acid ester, a substituted carboxamidegroup, or in the 4-position by nitro or a carbamic acid ester; W is anacetylenic group, and n is the integer 3.

Specifically preferred compounds of this invention according to Formula(I) for treating or controlling ras oncogene-dependent tumors andassociated proliferative diseases in warm-blooded animals preferablymammals, most preferably humans in need thereof are the followingcompounds or a pharmaceutically acceptable salt thereof:

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine-2,4-dione,

5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine-2,4-dione,

5-[11-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine-2,4-dione,

5-(4-Methoxyphenylsulfanyl)-5-(5-thiophen-2-yl-pent-4-ynyl)-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-fluorophenylsulfanyl)-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione,

5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione,

5-[11-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione,

5-[5-(2-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,

5-[5-(3-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(p-tolylsulfonyl)-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-fluorobenzenesulfonyl)-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(naphthalene-2-sulfonyl)-thiazolidine-2,4-dione,

N-(4-{5-[5-(4-Chlorophenyl)pent-4-ynyl]-2,4-dioxothiazolidine-5-sulfonyl}phenyl)acetamide,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(quinoline-8-sulfonyl)-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-nitrobenzenesulfonyl)-thiazolidine-2,4-dione,

5-(4-Benzyloxybenzenesulfonyl)-5-[5-(4-chlorophenyl)pent-4-ynyl]-thiazolidine-2,4-dione,

5-(4-Butoxybenzenesulfonyl)-5-[5-(4-chlorophenyl)-pent-4-ynyl]-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(naphthalene-1-sulfonyl)-thiazolidine-2,4-dione,

5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4-methoxy-benzenesulfonyl)-thiazolidine-2,4-dione,

5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiazolidine-2,4-dione,

5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-[4-(pyridin-4-yloxy)benzenesulfonyl]thiazolidine-2,4-dione,

5-[5-(2,4-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,

5-(4-Methoxybenzenesulfonyl)-5-[5-(3-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dione,

5-[5-(3-Nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)-thiazolidine-2,4-dione,

5-(4-Iodobenzenesulfonyl)-5-[5-(4-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dione,

5-(4-Methoxybenzenesulfonyl)-5-[5-(4-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dione,

5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methyl-5-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dione,

5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-5-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,

5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)-thiazolidine-2,4-dione,

5-(4-Iodobenzenesulfonyl)-5-[5-(2-methyl-5-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dione,

5-[5-(2-Methyl-5-nitrophenyl)-pent-4-ynyl]-5-(naphthalene-1-sulfonyl)-thiazolidine-2,4-dione,

5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(naphthalene-2-sulfonyl)-thiazolidine-2,4-dione,

5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-[4-(pyridin-4-yloxy)-benzenesulfonyl]-thiazolidine-2,4-dione,

5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzene-sulfonyl)-thiazolidine-2,4-dione,

5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)-pent-4-ynyl]-thiazolidine-2,4-dione,

5-(4-Iodobenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dione,

5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-4-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dione,

5-[5-(3-Fluoro-5-nitrophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,

5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiazolidine-2,4-dione,

5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,

5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,

5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiazolidine-2,4-dione,

5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)-thiazolidine-2,4-dione,

5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzene-sulfonyl)-thiazolidine-2,4-dione,

5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxy-benzenesulfonyl)-thiazolidine-2,4-dione,

5-[5-(4-Chloro-2-methylphenyl)-pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiazolidine-2,4-dione,

5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)-thiazolidine-2,4-dione,

5-[5-(4-Bromo-2-methy-phenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)-thiazolidine-2,4-dione,

5-[5-(4-Bromo-2-methylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiazolidine-2,4-dione,

(4-{5-[5-(4-Methoxybenzensulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}phenyl)carbamicAcid tert-Butyl Ester,

(3-Chloro-4-{5-[5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}phenyl)carbamic Acidtert-Butyl Ester,

N-tert-Butyl-3-{5-[5-(4-iodo-benzenesulfonyl)-2,4-dioxothiazol-idin-5-yl]-pent-1-ynyl}-4-methyl-benzamide,

(3-{5-[5-(4-Iodobenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]-pent-1-ynyl}-4-methylphenyl)carbamicAcid tert-Butyl Ester,

(4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}-3-methylphenyl)carbamicAcid tert-Butyl Ester,

(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid tert-Butyl Ester,

(4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-3-trifluoromethylphenyl)carbamicAcid tert-Butyl Ester,

N-tert-Butyl-3-{5-[5-(4-methoxy-benzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methyl-benzamide,

5-(4-Methoxybenzenesulfonyl)-5-[5-(4-trifluoromethylphenyl)pent-4-ynyl]-thiazolidine-2,4-dione,

5-(4-Methoxybenzenesulfonyl)-5-[5-(4-trifluoromethoxyphenyl)pent-4-ynyl]-thiazolidine-2,4-dione,

3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]-pent-1-ynyl}-4-methylbenzoicAcid Methyl Ester,

5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,

5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione,

4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}benzonitrile,

5-[5-(4-Methanesulfonylphenyl)-pent-4-ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione,

4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-3-methylbenzoicAcid Methyl Ester,

5-(4-Methoxybenzenesulfonyl)-5-[5-(4-pyrrol-1-yl-phenyl)pent-4-ynyl]-thiazolidine-2,4-dione,

5-(4-Iodo-benzenesulfonyl)-5-[5-(4-pyrrol-1-yl-phenyl)pent-4-ynyl]-thiazolidine-2,4-dione,

5-[5-(4-Pyrrol-1-ylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzenesulfonyl)-thiazolidine-2,4-dione,

5-(3-Methoxybenzenesulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)-thiazolidine-2,4-dione,

5-(4-Methylphenylsulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)-thiazolidine-2,4-dione,

5-(4-Methoxybenzenesulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)-thiazolidine-2,4-dione,

5-(4-Methoxybenzenesulfonyl)-5-(3-pyridin-3-ylprop-2-ynyl)-thiazolidine-2,4-dione,

5-(3-Thiophen-2-yl-prop-2-ynyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione,

5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione,

5-[3-(4-Phenoxyphenyl)prop-2-ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione,

5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,

5-(5-Pyridin-3-yl-pent-4-ynyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione,

5-[5-(5-Amino-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,

(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid Benzyl Ester,

(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid 4-Nitro-Benzyl Ester,

(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid 4-Chloro-phenyl Ester,

(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid Methyl Ester,

(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid Isopropyl Ester,

(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid Neopentyl Ester,

(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid Butyl Ester,

(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid Isobutyl,

N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2-methylpropanamide,

N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-3,3-dimethylbutanamide,

N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2,2-dimethylpropanamide,

N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2-phenylacetamide,

N-Benzyl-N′-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}1-pentynyl)-4-methylphenyl]urea,

N-(4-Methoxyphenyl)-N′-[3-(5-{5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,

N-(4-Chlorophenyl)-N′-[3-(5-{5-[(4-methoxy-phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,

N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)methylphenyl]-N′-(4-methylphenyl)urea,

4-Chloro-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,

4-Methoxy-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,

N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl][1,1′-biphenyl]-4-carboxamide,

4-(tert-Butyl)-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,

5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(5-chloro-2-thienyl)sulfonyl]-1,3-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)-4-pentynyl]-5-(2-thienylsulfonyl)-1,3-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(3,4-dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidine-2,4-dione,

5-[(5-Chloro-2-thienyl)sulfonyl]-5-[5-(2,5-dichlorophenyl)-4-pentynyl]-1,3-thiazolidine-2,4-dione,

5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-(2-thienylsulfonyl)-1,3-thiazolidine-2,4-dione,

5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-[(3,4-dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione,

5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidine-2,4-dione,

5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidine-2,4-dione,

tert-Butyl3-(5-{5-[(5-chloro-2-thienyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenylcarbamate,

tert-Butyl3-{5-[2,4-dioxo-5-(2-thienylsulfonyl)-1,3-thiazolidin-5-yl]-1-pentyn-yl}-4-methylphenylcarbamate,

tert-Butyl3-(5-{5-[(3,4-dimethoxy-phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenylcarbamate,

tert-Butyl3-[5-(2,4-dioxo-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidin-5-yl)-1-pentynyl]-4-methylphenyl-carbamate,

tert-Butyl3-[5-(2,4-dioxo-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidin-5-yl)1-pentynyl]-4-methylphenylcarbamate,

N-(tert-Butyl)-3-(5-{5-[(5-chloro-2-thienyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylbenzamide,

N-(tert-Butyl)-3-{5-[2,4-dioxo-5-(2-thienylsulfonyl)-1,3-thiazolidin-5-yl]-1-pentynyl}-4-methylbenzamide,

N-(tert-Butyl)-3-(5-{5-[(3,4-dimethoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylbenzamide,

N-(tert-Butyl)-3-[5-(2,4-dioxo-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidin-5-yl)-1-pentynyl]-4-methylbenzamide,

4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-3-methylbenzoicAcid,

N-(4-Chlorobenzyl)-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-4-yl]propionamide,

N-[2-(4-Chlorophenyl)ethyl]-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]propionamide,

5-[(4Z)-5-(4-Chloro-phenyl)pent-4-enyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione,

5-[(4E)-5-(4-Chlorophenyl)pent-4-enyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-[3-(4-Chlorophenyl)propyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,

5-[5-(3-Aminophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,

5-(3-Phenylalkyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione,

Enantiomerof(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid tert-Butyl Ester (less polar),

Enantiomer of(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid tert-Butyl Ester (more polar),

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfinyl)-thiazolidine-2,4-dione,

Benzyl5-[5-(5-{[(benzyloxy)carbonyl]-amino}-2-methylphenyl)pent-4-ynyl]-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,

4-Nitrobenzyl 5-[(4-methoxyphenyl)sulfonyl]-5-{5-[2-methyl-5-({[(4-nitro benzyl)oxy]carbonyl}amino)phenyl]pent-4-ynyl}-2,4-dioxo-1,3-thiazolidine-3-carboxylate,

Methyl5-(5-{5-[(methoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,

Isopropyl5-(5-{5-[(isopropoxycarbonyl)-amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,

Neopentyl5-[(4-methoxyphenyl)sulfonyl]-5-[5-(2-methyl-5-{[(neopentyloxy)carbonyl]-amino}phenyl)pent-4-ynyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,

Butyl5-(5-{5-[(butoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,

Isobutyl5-(5-{5-[(isobutoxycarbonyl)-amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(3-imidazol-1-yl-propyl)-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-3-methyl-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(2,4-diethoxybenzyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-3-(4-nitrobenzyl)thiazolidine-2,4-dione,and

5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidine-3-carboxylicacid 2-methoxy ethyl ester.

The present invention also discloses a process for the preparation of acompound of Formula (I):

wherein:

Ar is 1-naphthyl, 2-naphthyl, 8-quinolinyl, 2-thienyl,5-chloro-2-thienyl, 5-(2-pyridyl)-2-thienyl, 2-pyridinyl, substituted2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl, 2-pyrimidinyl,2-benzoxazolyl, 2-benzthiazolyl, 2-benzimidazolyl, 2-furanyl,2-benzo-[b]-furanyl, 2-benzo-[b]-thienyl or a moiety of the formula:

R₁ is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms,4-pyridyloxy, azido, nitro,acetamido, trifluoromethoxy, phenoxy, or benzyloxy;

R₂ is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, trifluoromethoxy, phenoxy, orbenzyloxy;

m is 0, 1 or 2;

R₆ is hydrogen;

Y is 2-methoxyethyl, alkyl is 1 to 6 carbon atoms, benzyl, orsubstituted benzyl;

W is

 E— and Z——CH═CH—, —CONH—, —CONHCH₂—, —CONHCH₂CH₂— or —CH₂—CH₂—;

n is an integer of 1 to 9;

Ar′ is thienyl, pyridinyl or a moiety of the formula:

R₃, R₄, R₅, are independently selected from hydrogen, alkoxy of 1 to 6carbon atoms, alkyl of 1 to 6 carbon atoms, fluoro, bromo, chloro, iodo,nitro, amino, hydroxy, azido, cyano, phenyl, phenoxy, trifluoromethyl,trifluoromethoxy, methanesulphonyl, 1-pyrrolyl, —CO₂R₇, —CONHR₈,—CH₂CONHR₉, —NHCO₂R₁₀, —NHCOR₁₁, and —NHCONHR₁₂;

R₇ is selected from H, and alkyl of 1 to 6 carbon atoms,

R₈ is selected from H, and alkyl of 1 to 6 carbon atoms;

R₉ is selected from H, and alkyl of 1 to 6 carbon atoms;

R₁₀ is selected from alkyl of 1 to 6 carbon atoms, benzyl, nitrobenzyl,and chlorophenyl;

R₁ is selected from alkyl of 1 to 6 carbon atoms, benzyl, phenyl,halophenyl, alkyl(1 to 6 carbon atoms)phenyl, alkoxy(1 to 6 carbonatoms)phenyl, and biphenyl;

R₁₂ is benzyl, alkyl of 1 to 6 carbon atoms, alkoxy(1 to 6 carbonatoms)phenyl, halophenyl, and alkyl(1 to 6 carbon atoms)phenyl;

provided that when W is

 then n is other than 2;

further provided that when n is 1, m is 0 or 2, R₆ is H and W is

 then:

Ar is not phenyl, 2-naphthyl, alkyl substituted phenyl, alkoxysubstituted phenyl, halogen substituted phenyl, 2-pyridinyl, substituted2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl, 2-pyrimidinyl,2-benzoxazolyl, 2-benzthiazolyl, 2-benzimidazolyl, 2-furanyl,2-benzo-[b]-furanyl, 2-thienyl, 2-benzo-[b]-thienyl; and

Ar′ is not phenyl, alkyl substituted phenyl, perfluoroalkyl (mono ordi)substituted phenyl, halogen substituted phenyl, alkoxy substitutedphenyl, perfluoroalkoxy substituted phenyl and alkylthio substitutedphenyl;

or pharmaceutically acceptable salts thereof,

which comprises:

reacting a compound of the formula:

with an alkyne of the formula:

Ar′W—(CH₂)_(m)—LG

wherein LG is a leaving group

in the presence of a base to give a compound of Formula (I) or apharmaceutically acceptable salt thereof.

It is understood that the definition of compounds of Formula (I) when R₁to R₁₂, contain asymmetric carbons, encompass all possible stereoisomersand mixtures thereof which possess the activity discussed below. Inparticular, the definition encompasses racemic modifications and anyoptical isomers which possess the indicated activity. Optical isomersmay be obtained in pure form by standard separation techniques orenantiomer specific synthesis. It is understood that this inventionencompasses all crystalline forms of compounds of Formula (I). Thepharmaceutically acceptable salts of the basic compounds of thisinvention are those derived from such organic and inorganic acids as:lactic, citric, acetic, tartaric, fumaric, succinic, maleic, malonic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, and similarly known acceptable acids. Where R₁ to R₁₂,or Y contains a carboxyl group, salts of the compounds in this inventionmay be formed with bases such as alkali metals (Na, K, Li) or alkalineearth metals (Ca or Mg).

For the compounds of Formula (I) defined above and referred to herein,unless otherwise noted, the following terms are defined:

Halogen, as used herein means chloro, fluoro, bromo and iodo.

Alkyl as used herein means a branched or straight chain having from 1 to6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.

Aryl as used herein means an aromatic radical wherein Ar is 1-naphthyl,2-naphthyl, 8-quinolinyl, 2-thienyl, 5-chloro-2-thienyl,5-(2-pyridyl)-2-thienyl, 2-pyridinyl, substituted 2-pyridinyl,3-pyridinyl, 4-pyridinyl, 2-quinolinyl, 2-pyrimidinyl, 2-benzoxazolyl,2-benzthiazolyl, 2-benzimidazolyl, 2-furanyl, 2-benzo-[b]-furanyl,2-benzo-[b]-thienyl or a moiety of the formula:

and further defined an aromatic radical Ar′ is thienyl, pyridinyl or amoiety of the formula:

Alkoxy as used herein means an —O-alkyl group in which the alkyl groupis as previously described. Exemplary alkoxy groups include methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy.

Alkyne as used herein means an alkynyl group

is present.

Phenyl as used herein refers to a 6-membered aromatic ring. Carbamicacid ester is —NHCO₂R₁₀ where preferred R₁₀ is alkyl of 1 to 6 carbonatoms.

Substituted carboxamide is —CONHR₈ wherein R₈ is alkyl of 0.1 to 6carbon atoms.

Substituted 2-pyridinyl and substituted benzyl, unless otherwiseprovided for herein, preferably has from 1 to 3 substituentsindependently selected from fluoro, chloro, bromo, iodo, nitro, cyano,alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms,trifluoromethyl and trifluoromethoxy.

This invention provides a method of treatment, by administration of aneffective amount of compounds of Formula (I), of ras oncogene-dependenttumors, which include cancers of the pancreas, colon, bladder, andthyroid; a method of controlling metastasis, suppressing angiogenesis,and inducing apoptosis; a method of treating Ras-associatedproliferative diseases other than cancer, which include restenosis,neuro-fibromatosis, endometriosis, and psoriasis The compounds ofFormula (I) may also inhibit prenylation of proteins other than Ras, andthus provide a method of treatment of diseases associated with otherprenyl modifications of proteins. The compounds of Formula (I) inhibitfarnesyl-protein transferase and the farnesylation of the oncogeneprotein Ras. Thus, this invention further provides a method ofinhibiting farnesyl protein transferase, (e.g., Ras farnesyl proteintransferase) in mammals, especially humans, by the administration of aneffective amount of the compounds of Formula (I). The administration ofthe compounds of this invention to patients, to inhibit farnesyl proteintransferase, is useful in the treatment of the cancers and otherdiseases described below.

This invention provides a method for inhibiting or treating the abnormalgrowth of cells, including transformed cells by administering aneffective amount of a compound of Formula (I). Abnormal growth of cellsrefers to cell growth independent of normal regulatory mechanisms (e.g.,loss of contact inhibition). This includes abnormal growth of tumorcells (tumors) expressing an activated Ras oncogene; tumor cells inwhich the Ras protein is activated as a result of oncogenic mutation inanother gene; and benign and malignant cells of other proliferativediseases in which aberrant Ras activation occurs.

This invention also provides a method for inhibiting or treating tumorgrowth by administering an effective amount of a compound of Formula(I), described herein, to a mammal (e.g., a human) in need of suchtreatment. In particular, this invention provides a method forinhibiting or treating the growth of tumors expressing an activated Rasoncogene by administration of an effective amount of a compound ofFormula (I). Examples of tumors which may be inhibited or treatedinclude, but are not limited to, lung cancer (e.g., lungadenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as,for example, exocrine pancreatic carcinoma), colon cancers (e.g.,colorectal carcinomas, such as, for example, colon adenocarcinoma andcolon adenoma), myeloid leukemias (for example, acute myelogenousleukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome(MDS), bladder carcinoma, epidermal carcinoma, breast cancer andprostate cancer.

This invention also provides a method for inhibiting or treatingproliferative diseases, both benign and malignant, wherein Ras proteinsare aberrantly activated as a result of oncogenic mutation in othergenes-i.e., the Ras gene itself is not activated by mutation to anoncogenic form-with said inhibition or treatment being accomplished bythe administration of an effective amount of a compound of Formula (I),to a mammal (e.g., a human) in need of such treatment. For example, thebenign proliferative disorder neurofibromatosis, or tumors in which Rasis activated due to mutation or overexpression of tyrosine kinaseoncogenes (e.g., neu, src, abl, Ick, and fyn), may be inhibited ortreated by the compounds of Formula (I). Additionally, this inventionprovides a method of inhibition or treating the abnormal growth ofcells, by administration of an effective amount of compounds of Formula(I), of ras-oncogene-dependent tumors, which tumors include cancers ofthe pancreas, colon, bladder, and thyroid. Without wishing to be boundby theory, these compounds may function through the inhibition ofG-protein function, such as ras p21, by blocking G-proteinisoprenylation, thus making them useful in the treatment ofproliferative diseases such as tumor growth and cancer. Without wishingto be bound by theory, compounds of Formula (I) inhibit Rasfarnesyl-protein transferase, and thus antiproliferative activity ofras-transformed cells and other prenyl modifications of proteins.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of this invention may be prepared according to the methods andprocedures described in U.S. Pat. Nos. 5,605,918 and 5,574,051, whichare hereby incorporated herein by reference; in Wrobel, J., et al., J.Med. Chem. 1998, 41 (7), 1084-91 and as outlined in Schemes I through XIdescribed herein.

As shown in Scheme I, arylthiol VI where Ar is hereinbefore defined isreacted with 2 or more equivalents of a strong base such as lithiumdiisopropylamide, lithium bis(trimethylsilylamide), and the likefollowed by reaction with one or more equivalents of5-bromothiazolidine-2,4-dione IV(Zask et al, J. Med. Chem. 1990, 33,1418-1423) to produce a 5-arylsulfanylthiazolidine-2,4-dione VII in anaprotic solvent such as tetrahydrofuran (THF) or hexane at temperatures(e.g. 0° to −78° C.) followed by warming to about ambient temperaturefor 1 to 10 h.

The 5-arylsulfanylthiazolidine-2,4-dione VII may then be oxidized toafford 5-arylsulfonylthiazolidine-2,4-dione V. Following the procedureof Zask et al (J. Med. Chem. 1990, 33, 1418-1423), the oxidation isconveniently performed using excess (2 to 20 equivalents) aqueoushydrogen peroxide in acetic acid at ambient or higher (30° to 80° C.)reaction temperatures for 1 to 10 h.

The 5-arylsulfanylthiazolidine-2,4-dione VII may also be oxidized toafford 5-arylsulfinylthiazolidine-2,4-dione Va by bubbling oxygen in thepresence of isobutyraldehyde in a solvent which includes acetonitrilefor 18 hours.

The 5-arylsulfonylthiazolidine-2,4-dione V may also be prepared byreacting one or more equivalents of an alkali metal arylsulfinate VIII,where M is an alkali metal with 5-bromothiazolidine-2,4-dione IV insuitable solvents which include polar aprotic solvents such asN,N-dimethylformamide (DMF), tetrahydrofuran (THF) or protic solventssuch as low molecular weight alcohols (methyl alcohol, ethyl alcohol andisopropanol and the like), or water.

Alternatively, the alkali metal arylsulfinate VIII can also be preparedby reduction of an arylsulfonyl chloride with sodium iodide in acetone(Harwood, Julia, and Thuillier, Tetrahedron, 1980,36, 2483-2487).

As shown in Scheme II arylalkynes XI, wherein Ar′ is as previouslydefined, and LG is a suitable leaving group which include iodo, bromoand p-toluenesulfonyloxy, can be prepared via a two step process fromcommercially available aryl iodides or aryl bromides where Ar′ ishereinbefore defined or those aryl iodides or aryl bromides described inthe the art. In the first step, alcohol X is prepared by the reaction ofthe appropriate aryl iodide or bromide with one or more equivalents of aterminal alkyne-ol IX, in the presence of a catalytic amount of apalladium(II) reagent such asdichlorobis(triphenylphosphine)palladium(II) and a catalytic amount of acopper(I) reagent such as copper(I) iodide. This reaction is alsoperformed in the presence of one or more equivalents of a secondary ortertiary amine such as diethylamine or triethylamine. The secondary ortertiary amine may be used as solvent, or alternatively a halocarbonsolvent such as chloroform may be employed. Temperatures up to 80° C.are commonly used, with reaction times varying from 1 h to 2 days.Alkyne XI wherein Ar′ is hereinbefore defined and LG isp-toluenesulfonyloxy is most conveniently prepared from alcohol X byreaction with p-toluenesulfonyl chloride in a solvent such asdichloromethane and in the presence of N,N-dimethylaminopyridine andtriethylamine at 0° C. to 30° C., from one hour to 6 hours; or when LGis iodo, alcohol X is reacted with iodine, in the presence oftriphenylphosphine and imidazole in a solvent such as ether, oracetonitrile, at a temperature of 0° C. to room temperature for 8 hoursto 24 hours; alternatively alkyne XI wherein LG is p-toluenesulfonyloxyis reacted with sodium iodide in acetone at room temperature from 8hours to 36 hours to give alkyne XI wherein LG is iodo; or when LG isbromo, X is reacted with carbon tetrabromide in the presence oftriphenylphosphine in a solvent such as THF at 0° C. to 35° C. for 8hours to 72 hours to give alkyne XI wherein LG is bromo.

Referring to Scheme III:5-substituted-5-(arylsulfanyl)thiazolidine-2,4-diones of Formula (I) maybe prepared by reaction of the appropriate5-(arylsulfanyl)thiazolidine-2,4-dione VII with 2 or more equivalents ofa base. Two equivalents of base effect deprotonation of both thethiazolidinedione nitrogen atom and at the C-5 position to form adianion. Common bases to accomplish this deprotonation include alkalimetal hydrides such as sodium hydride, alkali metal alkyls such as butyllithium or alkali metal amide bases such as lithium diisopropylamide orlithium bis(trimethylsilyl)amide. Convenient solvents include THF andDMF. Reaction temperatures may be varied from −78° C. to roomtemperature. Two minutes to 1 h after the base is introduced, one ormore equivalents of the appropriate alkylating agent, alkyne XI is addedto the reaction mixture and this is allowed to stir at 0° C. or roomtemperature for a period of from 1 h to 3 days. Alkylation occursprimarily on the thiazolidindione C-5 carbon atom to afford the5-substituted-5-(arylsulfanyl)thiazolidine-2,4-dione of Formula (I), m=0which may then be oxidized to afford5-arylsulfonylthiazolidine-2,4-dione of Formula (I) wherein m=2 by theprocedure of Zask et al (J. Med. Chem. 1990, 33, 1418-1423). Theoxidation is conveniently performed using excess (2 to 20 equivalents)aqueous hydrogen peroxide in acetic acid at ambient or higher (30° C. to80° C.) reaction temperatures for 1 to 10 h.

Referring to Scheme IIIa:5-substituted-5-(arylsulfinyl)thiazolidine-2,4-diones of Formula (I) maybe prepared by reaction of the appropriate5-(arylsulfinyl)thiazolidine-2,4-dione Va in the presence of a base.Common bases include alkali metal hydrides such as sodium hydride,alkali metal alkyls such as butyl lithium or alkali metal amide basessuch as lithium diisopropylamide or lithium bis(trimethylsilyl)amide.Convenient solvents include THF and DMF. Reaction temperatures may bevaried from −78° C. to room temperature. Two minutes to 1 h after thebase is introduced, one or more equivalents of the appropriatealkylating agent, alkyne XI is added to the reaction mixture and this isallowed to stir at 0° C. or room temperature for a period of from 1 h to3 days. Alkylation occurs primarily on the thiazolidindione C-5 carbonatom to afford the 5-substituted-5-(arylsulfinyl)thiazolidine-2,4-dioneof Formula (I), m =1.

As shown in Scheme IV:5-substituted-5-(arylsulfonyl)thiazolidine-2,4-diones of Formula (I) maybe prepared by reaction of the appropriate5-(arylsulfonyl)thiazolidine-2,4-dione V with 2 or more equivalents of abase. Two equivalents of base effect deprotonation of both thethiazolidinedione nitrogen atom and at the C-5 position to form adianion. Common bases to accomplish this deprotonation include alkalimetal hydrides such as sodium hydride, alkali metal alkyls such as butyllithium or alkali metal amide bases such as lithium diisopropylamide orlithium bis(trimethylsilyl)amide. Convenient solvents include THF andDMF. Reaction temperatures vary from −78° C. to room temperature. Twominutes to 1 h after the base is introduced, one or more equivalents ofthe appropriate alkylating agent, alkyne XI is added to the reactionmixture and the reaction is allowed to stir at 0° C. or room temperaturefor a period of from 1 h to 3 days. Alkylation occurs exclusively on thethiazolidindione C-5 carbon atom to afford the5-substituted-5-(arylsulfonyl)thiazolidine-2,4-dione of formula (I).

As shown in Scheme V, a compound of Formula (I), wherein at least one ofR₃, R₄, or R₅ of the moiety:

is a nitro group, and as shown in formula I′ where R₃ is a nitro group,is reacted with a reducing agent, such as iron in acetic acid or tin inhydrochloric acid, or other agents known to effect this reduction togive an amine XIII.

As further shown in Scheme V, compounds of Formula (I), wherein at leastone of R₃, R₄, or R₅ is amino, as shown in amine XIII can be prepared byhydrolysis of carbamate XII, wherein at least one of R₃, R₄, or R₅ ofFormula (I) is a t-butoxycarbonylamino group, by the use of an acid,such as trifluoroacetic acid, or aqueous hydrochloric acid at 0° C. to60° C., from 0.5 h to 4 h.

Substituted amine XIV, wherein at least one of R₃, R₄, or R₅ is—NHCO₂R₁₀ wherein R₁₀ is selected from alkyl of 1 to 6 carbon atoms,benzyl, nitrobenzyl, chlorophenyl; substituted amine XV, wherein atleast one of R₃, R₄, or R₅ is —NHCOR₁₁, wherein R₁₁ is selected fromalkyl of 1 to 6 carbon atoms, benzyl, phenyl, alkyl(1 to 6 carbonatoms)phenyl, alkoxy(1 to 6 carbon atoms)phenyl, biphenyl; substitutedamine XVI wherein at least one of R₃, R₄, or R₅ is —NHCONHR₁₂ whereinR₁₂ is benzyl, alkoxy(1 to 6 carbon atoms)phenyl, halophenyl, alkyl(1 to6 carbon atoms)phenyl can each be prepared by reaction of the amineXIII, respectively with an appropriate alkoxycarbonyl oraryloxycarbonylchloride; acid chloride, or similarly activated acylcompound; or an isocyanate, in an inert solvent, in the presence of anacid scavenger such as triethylamine, at 0° C. to 40° C., for 0.5 h to24 h.

Referring to Scheme VI: compounds of formula (I), wherein at least oneof R₃, R₄, or R₅ is the azido group, as in azide XVII may be preparedfrom amine XIII, by reaction with sodium nitrite in acetic acid at 0° C.to 20° C., for 10 min to 30 min, followed by a metal azide, such aslithium azide for 1 h to 3 h at 10° C. to 25° C.

Referring to Scheme VII: compounds of formula (I), wherein at least oneof R₃, R₄, or R₅ is a carboxyl group as in carboxylic acid XIX can beprepared from the corresponding ester, such as the methyl ester as inester XVIII by hydrolysis with a base such as potassium carbonate in asolvent such as methanol, or water, followed by acidification with anacid, such as hydrochloric acid.

Referring to Scheme VIII: Compounds of Formula (I), wherein Ar′ ishereinbefore define and at least one of R₃, R₄, or R₅ are as describedabove, and W is Z——CH═CH— in alkene XXI may be prepared from thecorresponding compounds of formula (I) wherein W is

in alkyne XX by reduction with hydrogen and a catalyst, such as platinumor palladium in a solvent such as an alcohol, or THF at 0° to 30° C. for½ to 8 h;

As shown in Scheme IX: compounds of Formula (I) as in alkene XXVI,wherein either R₃, R₄, and R₅ are as previously defined as substituentson Ar′, and W is E——CH═CH—, may be prepared by alkylation of5-arylsulfonylthiazolidine-2,4-dione V with an alkene XXV underconditions as described in Scheme III for the corresponding alkyne.Alkenes XXIV wherein W is E——CH═CH—, can be prepared by coupling aniodophenyl compound where Ar′ is hereinbefore defined with an E-stannaneXXII in the presence of tetrakistriphenyl-phosphine palladium(0) andcopper(I) iodide in a solvent such as DMF at room temperature for 1 h to3 days and subsequent conversion to alcohol XXIII to alkene XXIV,wherein LG is iodo, may be accomplished in a manner analogous to thatshown in Scheme II. A compound such as XXV, above, wherein LG is aleaving group, such as, bromo or iodo is used to alkylate5-arylsulfonylthiazolidine-2,4-dione V as described herein before inScheme III.

Referring to Scheme X: compounds of formula (I), wherein Ar′ is hereinbefore described and W is —CH₂—CH₂— as in dione XXVII, can be preparedfrom a compound of formula (I) wherein W is either

or E— or Z——CH═CH—, by hydrogenation in the presence of palladium orplatinum in a solvent such as methanol plus 5% water; alternatively,5-arylsulfonylthiazolidine-2,4-dione V can be alkylated with XXVIII togive dione XXVII.

Standard Pharmacological Test Procedures

The ability of the compounds of this invention to inhibit FPTase wasevaluated in the standard pharmacological in vitro test proceduresdescribed below. Data for representative examples is summarized in TableI.

Enzyme test procedure: FPTase inhibition in vitro assay was performedaccording to James, G. L., Brown, M. S., and Goldstein, J. L., Methodsin Enzymology, 1995, 255, 38-46; and Garcia, M. A., et al., J. Biol.Chem., 1993, 268, 18415-18420.

Materials—Purified FPTase (Moomaw, J. F. and Casey, P. J., J. Biol.Chem., 1992, 267, 17438-17443), purified His₆-Ras, inhibitor compoundsat 10 mg/ml or 10 mM in 100% DMSO, ³H-FPP (50,000 dpm/pmol) Amersham,TCA/SDS (6%/2%), TCA (6%), Glass fiber filters (0.22-0.45 m), vacuummanifold or 96 well filtration plates.

Methods—1. Dilute FPTase inhibitors from stock solutions to 2.5× in 2.5%DMSO, 10 mM DTT, 0.5% octyl-B-glucoside. 2. Solution #1 is added toFPTase reaction in a volume of 20 ml. 3. Standard reaction mix, 50 ml,contains 50 mM Tris (7.5), 10 mM ZnCl₂, 3 mM MgCl₂, 20 mM KCl, 5 mM DTT,0.2% octyl-B-glucoside, 1% DMSO, 40 mM His₆-Ras, 10 ng FPTase, andvarious concentrations of FPTase inhibitors. 4. Incubate for 30-90 minat 250° C. 5. Stop reactions with TCA/SDS (6%/2%), hold at 4° C. for45-60 min. 6. Filter by manifold or 96 well plate, wash filter 3-5× withTCA (6%). 7. Add scintillant to filters, measure ³H-FPP incorporationinto Ras protein.

Analysis of Results—Percent inhibition by test compounds is determinedby the following:

(cpm from precipitated Ras with test compounds)−(background cpm)×100=%inhibition.

(cpm from precipitated Ras without test compounds)−(background cpm)

Cell-based test procedure: Tumor inhibition in vitro assay was performedaccording to P. Skehan, R. Storeng, D. Scudiero, A. Monks, J. McMohan,D. Vistica, J. Warren, H. Bokesh, S. Kenney, and M. R. Boyd, J. Natl.Cancer Instit., 1990, 82 (13), 1107-1112; L. V. Rubinstein, R. H.Shoemaker, K. D. Paull, R. M. Simon, S. Tosini, P. Skehan, D. A.Scudiero, A. Monks, and M. R. Boyd, J. Natl. Cancer Instit., 1990, 82(13), 1113-1118; A. Monks, et al., J. Natl. Cancer Instit., 1991, 83,757-766; M. R. Boyd and K. D. Paull, Drug Development Res., 1995, 34,91-109; and S. P. Fricker and R. G. Buckley, Anticancer Research, 1996,16, 3755-3760.

Materials—Cell Lines: Human tumor cell lines LS174T, HTB39, LoVo andCaCo2. Cell Media: RPMI 1640 (or DMEM medium and McCoy's medium) with10% Fetal Bovine Serum supplemented with L-glutamine andPennicilin/Streptomycin. Compounds: Supplied usually as a 10 mM stock in100% DMSO. Normal Saline: 150 mM NaCl Trichloroacetic Acid (TCA): 50%(w/v) in water. Sulforhodamine (SRB): 0.4% (w/v) in 1% Acetic Acid. TrisBase: 10 mM in water.

Methods—Cells are plated at 2000 cells per well, per 200 μl media, andallowed to adhere overnight at 37° C. At 24 h post plating, compoundsare added directly at a volume of 0.5 μl. Compound is first diluted inDMSO to generate concentrations of compound or reference standard of: 1,5, 10 and 25 μM. Dilutions can be made in an identical 96 well plate sothat compounds can be added using a multichannel micropipettor set at0.5 μl. The cells are then incubated for four days after which the mediais removed using a 12 well manifold by first tipping the plate forwardat a 45 degree angle and then inserting the manifold in an uprightorientation to prevent the tips of the manifold from disturbing cells atthe bottom of the plate. 200 μl of normal saline is then added to eachwell using an 8 well multichannel pipettor, followed by the carefuladdition of 50 μl of 50% TCA. The plates are then incubated for 2 h at4° C., after which the supernatant is removed using the same techniqueas above and the plates washed twice with 200 μl water. The plates arethen air dried and 50 μl of SRB stock solution is carefully added sothat the entire bottom of each well is covered. This again can be usedusing an 8 well multichannel pipettor. The SRB is incubated with fixedcells for 15 min at room temperature, after which the SRB is removedwith the manifold as described above and the plates washed twice with350 μl of 1% acetic acid per well each time. The plates are then airdried after which the bound SRB is released from protein by the additionof 200 μl of Tris base. Resolubilizing the SRB is aided by placing theplates on a rotator for 15-30 min. The absorbance of each well isdetermined at 550 or 562 nm using a microtiter plate reader.

Analysis of Results—Each compound or dilution thereof is performed intriplicate. Outliers are identified by visual inspection of the data.Each plate should have a control (vehicle only). A standard curve isconstructed by plotting the concentration of compound against theaverage absorbance calculated at that concentration. A curve is plottedand the concentration at which the curve passes through the 50%absorbance mark seen in the control well is the IC₅₀ calculated for thatcompound.

TABLE I in vitro FTase Inhibition Assay IC₅₀ H-Ras* IC₅₀ K-Ras* Ex. No.μM μM 96 0.7 97 0.075-0.15  3.5-5.5 101 0.01-0.03 0.11-1.0  102 0.03-0.032 1.4 103 0.03-0.05 0.9-10  104  0.03-0.054 0.23-0.9  1050.05-0.15 1.5-1.7 106 0.23-0.25 1.3-1.7 107 0.18-0.2  0.62-0.7  1080.13-0.18    9->10  109 0.065-0.13  1.4-2.1 110 0.4 7   111 0.11-0.15 0.3-0.55 112 0.59-0.60 1.4-1.5 113 0.05-0.06 0.75-0.8  114 0.013-0.0320.032-0.32  115 0.012-0.32  0.16-0.23 116 0.005-0.01  0.017-0.04  1170.02-0.03 0.51-1.0  118 0.07 1.9 119 0.13-0.14 1.3-1.7 120 0.018-0.0320.53-1.0  121 0.12 1.6 122 0.03-0.05 0.23-1.0  123  0.08-0.082 1.0-2.8124 0.052-0.08  0.91-1.3  125 0.03 0.4 126 0.09 1.7 127 0.12-0.141.3-1.5 128 0.001-0.032 0.02-0.22 129 0.1  0.6-0.79 130 0.023-0.0560.32-1.0  131 0.006-0.032 0.08-0.31 132 0.041-0.073 0.21-1.0  1330.04-0.2  0.054-1.0  134 0.014-0.85  0.43-0.68 135  0.02-0.032 1.9-2.1136 0.043-0.05  1.0-1.9 137 0.021-0.4  0.037-0.8  138 0.023-0.032 0.3-0.42 139 0.17-0.14 0.6-5.0 140 0.15-0.3  1.0-3.6 141 0.021-0.0320.30-0.34 142 0.017-0.03  0.04-1.0  143 0.03  0.85 144  0.04-0.0410.32-0.55 145 1.2-1.7 5.6-10  147 0.0068-0.21  0.08-0.1  1480.0045-0.12  0.023-0.031 149 0.45-0.5  1.0-4.9 150 0.0074-0.032 0.016-0.068 151 0.53-0.7  0.21-1.0  152 0.011-0.016  0.1-0.23 1530.17-0.2  1.0-6.1 154 0.07-0.15 1.0-2.5 155 0.01-0.32 0.42-0.44 157 0.275.0 158 0.15 3.8 159 0.65 >10     161 0.9 10    162 1.21 4.0 163 1.310    164 0.15 >10     166 0.15 5.3 167 1.5 10    168 0.28 10    169 0.11.8 170 0.38 4.7 171 0.2 3.3 175  0.01-0.032 0.053-0.52  1760.0032-0.032  0.03-0.32 177 0.011-0.032 0.086-0.1  178 0.017-0.032  0.01179 0.002-0.032 0.005-0.07  180 0.002-0.032 0.007-0.09  181  0.01-0.0320.10-0.13 182 0.005-0.01  0.032-0.056 189 0.10 1.2 217 0.10 8.5 220 0.093.0 222 0.0033   0.033 223 0.063 >1    226 0.03-0.05 0.1-3.2 2270.007-0.01  0.21-0.4  228 0.004-0.07  0.23-1   229 0.006-0.02  0.1-0.7230  0.003-0.0035 0.02-0.5  231  0.01-0.021 0.1-1   232 0.005-0.01 0.04-0.64 233 2.9 10    *H-Ras or K-Ras used as substrates forfarnesylation

Compounds of this invention were tested in cell-based assays againsthuman tumor cell lines DLD-1 and LoVo and ras-transformed rat fibroblastcell lines, RAT-H-ras and RAT-K-ras, and the parent cell line RAT-2, asdescribed under Assays. The range observed for inhibition of cell growthwas IC₅₀=7 to 18 μM. The results are displayed in Table I.

Compounds of this invention were tested for in vivo effects in ratsagainst various tumors. For the compound of Example 114, when testedagainst a K-ras dependent human colon carcinoma (LoVo), the followingresults were obtained (Table II):

TABLE II In Vivo Data for the Compound of Example 114 a Drug Treatment bb b b b mg/kg Day c d Day c d Day c D Day c d Day c d e per dose 8 % T/C(p) 15 % T/C (p) 22 % T/C (p) 29 % T/C (p) 36 % T/C (p) S/T 0.5% 88 308598 748 1264 10/10 Methocel 0.4% Tween 80 Cpd. 61 70 0.10 238 77 0.14454 76 0.08 608 81 0.20 934 74 0.09 10/10 (100 PO) Cpd. 45 51 0.02 11036 <.01 255 43 <.01 504 67 0.09 764 60 0.03  8/10 (75 IP) Cpd. 65 740.15 146 47 0.02 258 43 <0.01 445 59 0.07 964 76 0.16  5/10 (50 IP) Cpd.31 35 <0.01 125 41 <.01 251 42 <.01 341 46 0.01 559 44 0.01  9/10 (100IP) Vincristine 14 16 <0.01 24 8 <.01 84 14 <.01 139 19 <0.01 194 15<.01  9/10 (1 IP) 2% Tween 39 121 198 287 424 10/10 in D5W Cpd. 86 2210.95 182 150 0.84 324 163 0.92 478 167 0.92 666 157 0.91 10/10 (75* IP)20% BCD 62 146 339 499 813 10/10 in 0.1 N HCl Cpd. 50 81 0.22 138 950.44 299 88 0.31 641 128 0.77 872 107 0.60  9/10 (100 PO) a) Compound ofExample 114(100 IP) administered once a day on days 1 through 20. Allother doses of cpd. Were administered on days 1 through 20 BID.Vincristine administered on days 5, 9 and 13. prepared in 2% Tween 80 inD5W. b) Mean Tumor Weight in mg. c) % T/C = Mean Tumor Weight of TreatedGroup × 100 Mean Tumor Weight of Placebo Group d) Statistical analysis(Student's t-test) of Tumor Weight. A p-value (p ≦ 0.05) indicates astatistical significant reduction in Tumor. Weight of Treated Group,compared to Placebo Control. e) S/T = No. Survivors/No.Treated on Day+35 post tumor cell implantation

Examples 100, and 103, when tested in rats against Rat-2 fibroblaststransformed by oncogenic H-ras for 11 days, i.p., the following resultswere obtained for day 11 (Table IV):

TABLE III Ex. No. Dose, mg/kg % T/C 100 100 44 100 30 60 100 10 100 103100 No efficacy at this dose${\% \quad {TC}} = {\frac{\text{Mean~~Tumor~~Weight~~of~~Treated~~Group}}{\text{Mean~~Tumor~~Weight~~of~~Placebo~~Group}} \times 100}$

In a similar model when tested in rats against Rat-2 fibroblaststransformed by oncogenic K-ras for 25 days, i.p, the compound of Example100 showed no efficacy at 100 mg/kg.

Based on the results of these standard pharmacological test procedures,the compounds of this invention are useful as agents for treating,inhibiting or controlling ras-associated diseases by inhibitingfarnesyl-protein transferase enzyme, when administered in amountsranging from about 10 to about 200 mg/kg of body weight per day. Apreferred regimen for optimum results would be from about 10 mg to about100 mg/kg of body weight per day and such dosage units are employed thata total of from about 100 mg to about 1000 mg of the active compound fora subject of about 70 kg of body weight are administered in a 24 hourperiod.

The dosage regimen for treating mammals may be adjusted to provide theoptimum therapeutic response. For example, several divided doses may beadministered daily or the dose may be proportionally reduced asindicated by the exigencies of the therapeutic situation. A decidedlypractical advantage is that these active compounds may be administeredin any convenient manner such as by the oral, intravenous, intramuscularor subcutaneous routes.

The active compounds may be orally administered, for example, with aninert diluent or with an assimilable edible carrier, or they may beenclosed in hard or soft shell gelatin capsules, or they may becompressed into tablets or they may be incorporated directly with thefood of the diet. For oral therapeutic administration, these activecompounds may be incorporated with excipients and used in the form ofingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers and the like. Such compositions andpreparations should contain at least 0.1% of active compound. Thepercentage of the compositions and preparations may, of course, bevaried and may conveniently be between about 2% to about 60% of theweight of the unit. The amount of active compound in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained. Preferred compositions or preparations according to thepresent invention are prepared so that an oral dosage unit form containsbetween 10 and 1000 mg of active compound. The tablets, troches, pills,capsules and the like may also contain the following: a binder such asgum tragacanth, acacia, corn starch or gelatin; excipients such asdicalcium phosphate; a disintegrating agent such as corn starch, potatostarch, alginic acid and the like; a lubricant such as magnesiumstearate; and a sweetening agent such as sucrose, lactose, or saccharinmay be added or a flavoring agnet such as peppermint, oil of wintergreenor cherry flavoring. When the dosage unit form is a capsule, it maycontain, in addition to materials of the above type, a liquid carrier.Various other materials may be present as coatings or to otherwisemodify the physical form of the dosage unit. For instance, tablets,pills or capsules may be coated with shellac, sugar or both. A syrup orelixir may contain the active compound, sucrose, as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anydosage unit form should be pharmaceutically pure and substantiallynon-toxic in the amounts used. In addition, these active compounds maybe incorporated into sustained-release preparations and formulations.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols, and mixtures therof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth or microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and starage and must be prepared against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpoly-ethylene glycol), suitable mixtures thereof, and vegetable oils.

The present invention accordingly provides a pharmaceutical compositionwhich comprises a compound of Formula (I) of this invention incombination or association with a pharmaceutically acceptable carrier.In particular, the present invention provides a pharmaceuticalcomposition which comprises an effective amount of a compound of thisinvention and a pharmaceutically acceptable carrier.

As used in accordance with this invention, the term providing aneffective amount of a compound means either directly administering suchcompound, or administering a prodrug, derivative, or analog which willform an effective amount of the compound within the body.

The present invention provides a method of treatment of rasoncogene-dependent tumors, such as cancers of the pancreas, colon,bladder, and thyroid; a method of controlling metastasis, suppressingangiogenesis, and inducing apoptosis; a method of treatingRas-associated proliferative diseases other than cancer, such asrestenosis, neuro-fibromatosis, endometriosis, and psoriasis. Thecompounds of the present invention may also inhibit prenylation ofproteins other than Ras, and thus provide a method of treatment ofdiseases associated with other prenyl modifications of proteins.

The invention will be more fully described in conjunction with thefollowing specific examples which are not to be construed as limitingthe scope of the invention.

EXAMPLE 1 5-(3-Methoxyphenyl-4-sulfonyl)-thiazolidine-2,4-dione

To a solution of 5-bromothiazolidine-2,4-dione (6.66 g, 34.0 mmol, Zasket al, J. Med. Chem. 1990, 33, 1418-1423) and 3-methoxybenzenethiol(5.00 g,35.7 mmol)in dry THF (150 mL) at −78° C. was added sodiumbis(trimethylsilyl)amide (1.0M in THF, 56 mL, 56 mmol) dropwise. After30 min. the reaction mixture was warmed to room temperature. After anadditional hour, 2N HCl was added to pH=1. The layers were separated andthe aqueous phase was extracted with ethyl acetate.

The combined organic phase was dried (MgSO4), concentrated and flashchromatographed (3:1 hexanes:ethyl acetate) to provide5-(3-methoxyphenyl-4-sulfanyl)thiazolidine-2,4-dione, as a white solid(4.86 g, 56%); a sample of5-(3-methoxyphenyl-4-sulfanyl)-thiazolidine-2,4-dione (4.70 g, 18.4mmol) was oxidized with 9.4 ml of 30% hydrogen peroxide in 50 ml ofacetic acid at 45° C. for 3 hours to give 3.4 g (64%) of the titlecompound as a glass; NMR(CDCl₃)δ3.9 (s,3H), 5.53 (s,1 H), 7.3 (m,1 H),7.42 (s,1 H), 7.53 (m,2H); MS m/Z 285.9 (M−H) (calcd. For C₁₀H₉NO₅S₂)

EXAMPLE 2 5-(4-Fluorophenyl-4-sulfonyl)-thiazolidine-2,4-dione

In the manner of Example 1 above 4-fluorobenzenethiol andbromothiazolidinedione gave5-(4-fluorophenyl-4-sulfanyl)-thiazolidine-2,4-dione, which on oxidationgave the title compound [U.S. Pat. No. 5,605,918; February 1997; Wrobel,et al.].

EXAMPLE 3 5-(4-Iodophenyl-4-sulfonyl)-thiazolidine-2,4-dione

To a solution of 5-bromothiazolidinedione (5.94 g, 30.3 mmol) in 100 mlof absolute ethanol was added sodium 4-iodophenylsulfinate (9.67 g, 33.3mmol)and this slurry was stirred for about 18 hours at room temperature.Solvent was removed and the residue was combined with water and wasacidified with 2N hydrochloric acid. The organic portion waschromatographed on silica gel with hexanes-ethyl acetate (3:1) to give5.8 g (50%) of the title compound, mp 190-193° C.

In a like manner to the procedure of Example 3 above, the following arylsulfinate salts which are either commercially available, or are preparedby the reduction of the corresponding sulfonyl chloride with sodiumiodide in acetone (Harwood, Julia, and Thuillier, Tetrahedron, 1980,36,2483-2487), were reacted with 5-bromothiazolidinedione to give theindicated product, 5-arylsulfonylthiazolidinediones of Examples 4-17:

EX. No. SULFINATE SALT PRODUCT MELTING POINT ° C. 4 Sodium 4-Trifluoro-5-(4-Trifluoromethoxy- 108-110 methoxybenzenesulfinatebenzenesulfonyl)thiazol- idine-2,4-dione 5 Sodium 3-Nitrobenzene5-(3-Nitrobenzenesulfonyl)- 139-140 sulfinate thiazolidine-2,4-dione 6Sodium 4-Nitrobenzene 5-(4-Nitrobenzenesulfonyl)- 182-183 sulfinatethiazolidine-2,4-dione 7 Sodium 4-(Pyridin-4- 5-[4-(Pyridin-4-yloxy)-160 with yloxy)benzenesulfinate benzenesulfonyl]-thiazolidine-2,4-decomp. dione 8 Sodium 4-Phenoxy- 5-(4-Phenoxybenzene sulfonyl)- 160-162benzene-sulfinate thiazolidine-2,4-dione 9 Sodium 4-Benzyloxy-5-(4-Benzyloxybenzene- 190-200 benzenesulfinatesulfonyl)-thiazolidine-2,4-dione decomp. 10 Sodium 3,4-Dimethoxy-5-(3,4-Dimethoxybenzene- 220-222 benzene sulfinatesulfonyl)-thiazolidine-2,4-dione 11 Sodium N-Acetyl-3-amino-N-[5-(2,4-Dioxothiazolidine-5- 217-219 4-methoxyphenyl-sulfinatesulfonyl)-2-methoxy-phenyl]- acetamide 12 Sodium 5-Chloro-5-(5-Chloro-thiophene-2- 133-135 thiophene-2-sulfinatesulfonyl)-thiazolidine-2,4-dione 13 Sodium Thiophene-2-5-(Thiophene-2-sulfonyl)- 176-177 sulfinate thiazolidine-2,4-dione 14Sodium 5-Pyridin-2-yl- 5-(5-Pyridin-2-yl-thiophene-2- 168-170thiophene-2-sulfinate sulfonyl)-thiazolidine-2,4-dione 15 Sodium4-Butoxybenzene 5-(4-Butoxybenzenesulfonyl)- 120-121 sulfinatethiazolidine-2,4-dione 16 Sodium 1-Naphthalenyl)5-[(1-Naphthalenyl)sulfonyl]-2,4- 187-188 sulfinate thiazolidinedione 17Sodium (8-Quinolinyl) 5-[(8-Quinolinyl)sulfonyl]-2,4- amorphoussulfinate thiazolidinedione solid

EXAMPLE 18 5-(2,5-Dichlorophenyl)pent-4-yn-1-ol

A solution of 1,4-dichloro-2-iodobenzene (20.0 g, 73.3 mmol),4-pentyn-1-ol (6.17 g, 73.3 mmol), bistriphenylphosphine(Pd II) chloride(1.03 g, 1.47 mmol), and copper(I) iodide (0.14 g, 0.733 mmol) in 400 mlof diethylamine was stirred under nitrogen for three days. This wasdiluted with dichloromethane and the oily layer was adsorbed onto silicagel and eluted with hexanes-ethyl acetate (5:1) to give5-(2,5-dichloro-phenyl)pent-4-yn-1-ol, 13.7 g (82%); NMR (CDCl3) δ1.9(m,2H), 2.6 (t,2H), 3.85 (t,2H), 7.2 (dd,1 H), 7.28 (m,1 H), 7.4 (d,2H).

EXAMPLE 19 5-(4-Methanesulfonylphenyl)pent-4-yn-1-ol

Preparation of the title compound with 4-bromophenyl methyl sulphone(5.87 g, 25 mmol) and 4-pentyn-1-ol (2.1 g, 25 mmol) according to theprocedure in example 18 yielded 5.12 g (87%) of yellow oil which wascharacterized as 5-(4-Methanesulfonylphenyl)pent-4-yn-1-ol: NMR (CDCl₃)δ 1.88-1.93 (m,2H), 2.56-2.60 (t, J=6.99, 2H), 3.04 (s,3H), 3.80-3.84(t, J=6.15,2H), 7.56 (d, J=5.1,2H), 7.85(d,J=4.8,2H). MS m/Z 239 (M+Hcald. for C₁₂H₁₄O₃S 238.3)

In a manner described in Example 19 immediately above the followingacetylenic alcohols of Examples 20-48 were prepared from thecorresponding iodobenzene or bromobenzene and 4-pentyn-1-ol (structureswere confirmed as above by NMR):

EX. No. PRODUCT Mass Spectrum M+ 205-(2-Methyl-5-nitrophenyl)pent-4-yn-1-ol      220 (M + H)  215-(2-Methoxy-5-nitrophenyl)pent-4-yn-1-ol 235.0 225-(2-Methoxy-4-nitrophenyl)pent-4-yn-1-ol 235.0 235-(4-Nitro-2-trifluoromethylphenyl)pent-4-yn-1-ol 273.0 245-(3-Fluoro-5-nitrophenyl)pent-4-yn-1-ol 223.0 255-(3-Fluoro-4-methoxy-5-nitrophenyl)pent-4-yn-1-ol      254.2 (M + H) 265-(4-Methoxy-2-nitrophenyl)pent-4-yn-1-ol      234.2 (M + H) 27[3-Chloro-4-(5-hydroxypent-1-ynyl)phenyl]-carbamic Acid tert-Butyl Ester28 5-(4-Pyrrol-1-ylphenyl)pent-4-yn-1-ol      226.2 (M + H) 295-(2,5-Dimethylphenyl)pent-4-yn-1-ol      189.1 (M + H) 305-(5-Chloro-2-methylphenyl)pent-4-yn-1-ol      208.8 (M + H) 315-(4-Chloro-2-methylphenyl)pent-4-yn-1-ol 208.0 325-(2,4-Dimethylphenyl)pent-4-yn-1-ol 188.1 335-(2-Methyl-4-nitrophenyl)pent-4-yn-1-ol 219.0 345-(4-Bromo-2-methylphenyl)pent-4-yn-1-ol 253.0 353-(5-Hydroxypent-1-ynyl)-4-methylbenzoic Acid Methyl 232.1 Ester 364-(5-Hydroxypent-1-ynyl)-3-methylbenzoic Acid Methyl 232.1 Ester 375-(4-tert-Butylphenyl)pent-4-yn-1-ol 38[4-Methyl-3-(5-hydroxypent-1-ynyl)phenyl] carbamic Acid tert-Butyl Ester39 5-(2-Chlorophenyl)pent-4-yn-1-ol 405-(2,4-Dichlorophenyl)pent-4-yn-1-ol 414-(5-Hydroxypent-1-ynyl)trifluoromethyl benzene 424-(5-Hydroxypent-1-ynyl)trifluoromethoxy-benzene 43[3-Methyl-4-(5-hydroxypent-1-ynyl)phenyl] carbamic Acid tert-Butyl Ester44 N-tert-Butyl-3-(5-hydroxypent-1-ynyl)-4- methylbenzamide 454-(5-Hydroxypent-1-ynyl)phenylcarbamic Acid tert-Butyl Ester 463-(5-Hydroxypent-1-ynyl)-4-methylbenzoic Acid Methyl Ester 475-(4-Chlorophenyl)pent-4-yn-1-ol 48 5-(3-Chlorophenyl)pent-4-yn-1-ol

EXAMPLE 49 6-(4-Chlorophenyl)hex-5-yn-1-ol

In a manner described in Example 18 above, 5-hexyn-1-ol was reacted with1-chloro-4-iodobenzene to give the title compound, MS m/Z exact mass209.724 (M+H)(calcd. For C₁₂H₁₃OCl 209.70).

EXAMPLE 50 11-(4-Chlorophenyl)undec-10-yn-1-ol

In a manner described in Example 18 above, 10-undecene-1-ol was reactedwith 1-chloro-4-iodobenzene to give the title compound; NMR (CDCl₃)δ1.21-1.50 (m, 10H), 1.50-1.65 (m, 4H), 2.36-2.41 (m,2H),3.61-3.66(m,2H), 7.16-7.31 (m, 4H).

EXAMPLE 51 3-(4-Phenoxyphenyl)prop-2-yn-1-ol

Preparation of the title compound with commercial available4-bromo-diphenyl ether (5.93 g, 23.8 mmol) according to the procedure inexample 18 yielded 440 mg (8.2%) of brown oil which was characterized as3-(4-phenoxyphenyl)prop-2-yn-1-ol: NMR (CDCl₃) δ4.50 (d, J=6), 6.91 (d,J=2.01, 1H), 6.93 (d, J=2.01, 1H), 7.01 (d, J=0.63, 1H),7.04 (d, J=1.17,1H), 7.11-7.16 (m, 1H),7.36 (d, J=0.6, 1H), 7.38 (d, J=2.52, 2H), 7.41(d, J=1.92, 1H). MS m/z 224.08 (M+calcd. for C₁₅H₁₂O₂=224.08).

EXAMPLE 52 3-Biphenyl-4-yl-prop-2-yn-1-ol

In a manner described in Example 18 above, propargyl alcohol was reactedwith 4-bromobiphenyl to give the title compound as white crystals: NMR(CDCl₃) δ 4.53 (d, J=4.74, 2H), 7.38 (d, J=7.17, 1H), 7.42-7.60 (m, 8H).MS m/z 208 (M+ calcd. for C₁₅H₁₂O=208.3).

EXAMPLE 53 3-Thiophene-2-yl-prop-2-yn-1-ol

In a manner described in Example 18 above, propargyl alcohol was reactedwith 2-bromothiophene to give the title compound as a brown oil whichwas used in the next step without further purification.

EXAMPLE 54 1-Chloro-4-(5-iodopent-1-ynyl)benzene

5-(4-Chlorophenyl)pent-4-yn-1-ol (35.7 g, 182 mmol),4-dimetylamino-pyridine (8.9 g, 73 mmol), p-toluenesulfonyl chloride(34.7 g, 182 mmol), and 62 ml of triethylamine were combined in 330 mlof dichloromethane at 0° C. The mixture was stirred for 30 min. at 0°then 18 hours at room temperature. Dilution with 200 ml ofdichloromethane followed by washing with brine, drying over magnesiumsulfate, filtration through silica gel with hexane-ethyl acetate, 8:1,gave a yellow solid on evaporation. Crystallization from ether gave5-(4-Chlorophenyl)pent-4-yn-1-ol p-toluenesulfonate as colorlesscrystals (31.7 g, 49% yield). This was converted to the title compoundby reaction with sodium iodide in acetone, and was used in subsequentreactions with no further purification; MS m/z 303.9 (M+ calcd. forC₁₁H₁₀CII=304.6).

EXAMPLE 55 1-(5-Iodo-pent-1-ynyl)-4-methanesulfonylbenzene

Preparation of the title compound with tosylated alcohol of example 19,5-(4-methanesulfonylphenyl)pent-4-yn -1-ol (3.14 g, 8.35 mmol), Nal(6.26 g, 41.76 mmol) following the procedure of Example 54 yielded 2.8 g(96%) of the title compound as a red oil: NMR (CDCl₃) δ 2.06-2.15 (m,2H), 2.58-2.63 (t, J=6.78, 2H), 3.04 (s, 3H), 3.33-3.37 (t, J=6.69, 2H),7.57 (d, J=1.77, 2H), 7.85 (d, J=4.95, 2H), MS m/z 348.9 (M+H cald. forC₁₂H₁₃IO₂S 348=349.2).

EXAMPLE 56 1,4-Dichloro-2-(5-iodopent-1-ynyl)benzene

5-(2,5-Dichlorophenyl)pent-4-yn-1-ol (13.7 g, 59.8 mmol),triphenylphosphine (20.4 g, 77.8 mmol), and imidazole (5.71 g, 83.8mmol) in a mixed solvent (100 ml acetonitrile-150 ml ether) was stirredunder nitrogen at 0° C., and to this was slowly added iodine (21.3 g,83.8 mmol). The solution was allowed to warm to room temperature andstirring was continued for 18 hours. This was chromatographed on silicagel with hexane to give the title compound (14.7 g,72%), MS m/z 337.9(M−H calcd. for C₁₁H₉Cl₂I=338.0).

In the manner described in Example 55, above, the following alcoholswere converted to the corresponding iodides of Examples 56-88, andstructures were confirmed as above by NMR:

EX. No. ALCOHOL PRODUCT MASS SPECTRUM 56 5-(2,4-Dichlorophenyl)-pent-1,5-Dichloro-2-(5-iodo- 337.9 4-yn-1-ol pent-1-ynyl)benzene 575-(2-Methyl-5-nitro- 2-(5-Iodopent-1-ynyl)-1- 330 phenyl)pent-4-yn-1-olmethyl-4-nitro-benzene 58 5-(2-Methoxy-5-nitro- 2-(5-Iodopent-1-ynyl)-1-345.1 phenyl)pent-4-yn-1-ol methoxy-4-nitro-benzene 595-(2-Methoxy-4-nitro- 1-(5-Iodopent-1-ynyl)-2- 345.0phenyl)pent-4-yn-1-ol methoxy-4-nitro-benzene 605-(4-Nitro-2-trifluoro-methyl- 1-(5-Iodopent-1-ynyl)-4- 383.0phenyl)pent-4-yn-1-ol nitro-2-trifluoro- methylbenzene 615-(3-Fluoro-5-nitro- 1-Fluoro-3-(5-iodopent-1- 334 phenyl)pent-4-yn-1-olynyl)-5-nitrobenzene 62 5-(3-Fluoro-4-methoxy-5-1-Fluoro-5-(5-iodopent-1- nitrophenyl)pent-4-yn-1-ol ynyl)-2-methoxy-3-nitrobenzene 63 5-(4-Methoxy-2-nitro- 1-(5-Iodopent-1-ynyl)-4-phenyl)pent-4-yn-1-ol methoxy-2-nitro-benzene 64[3-Chloro-4-(5-hydroxy-pent- [3-Chloro-4-(5-iodo-pent-1- [mp 104-1-ynyl)-phenyl]-carbamic ynyl)phenyl]-carbamic acid 106° C.] acidtert-butyl ester tert-butyl ester 65 5-(4-Pyrrol-1-yl-phenyl)-pent-1-[4-(5-Iodopent-1-ynyl)- 335.7 4-yn-1-ol phenyl]-1H-pyrrole 665-(2,5-Dimethylphenyl)- 1-(5-Iodopent-1-ynyl)-2,5- 298.0 pent-4-yn-1-oldimethyl-benzene 67 5-(5-Chloro-2-methyl- 4-Chloro-2-(5-iodopent-1-317.9 phenyl)-pent-4-yn-1-ol ynyl)-1-methyl-benzene 685-(4-Chloro-2-methyl- 4-Chloro-1-(5-iodopent-1- 317.9phenyl)pent-4-yn-1-ol ynyl)-2-methyl-benzene 695-(2,4-Dimethyl-phenyl)pent- 1-(5-Iodopent-1-ynyl)-2,4- 298.0 4-yn-1-oldimethyl-benzene 70 5-(2-Methyl-4-nitro-phenyl)- 1-(Iodopent-1-ynyl)-2-328.9 pent-4-yn-1-ol methyl-4-nitrobenzene 715-(4-Bromo-2-methyl-phenyl) 4-Bromo-1-(5-iodopent-1- 361.9pent-4-yn-1-ol ynyl)-2-methyl-benzene 72 3-(5-Hydroxypent-1-ynyl)-4-3-(5-Iodopent-1-ynyl)-4- 341.9 methylbenzoic acid methyl methylbenzoicacid methyl ester ester 73 4-(5-Hydroxy-pent-1-ynyl)-3-3-(5-Iodopent-1-ynyl)-4- 341.9 methylbenzoic acid methyl methylbenzoicAcid Methyl ester Ester 74 [4-Methyl-3-(5-hydroxypent-[3-(5-Iodopent-1-ynyl)-4- 399.9 1-ynyl)phenyl]carbamic acidmethylphenyl]carbamic tert-butyl ester acid tert-butyl ester 755-(2-Chlorophenyl)-pent-4- 1-Chloro-2-(5-iodopent-1- 304.0 yn-1-olynyl)benzene 76 5-(2,4-Dichlorophenyl)pent- 2,4-Dichloro-1-(5-iodo-337.9 4-yn-1-ol pent-1-ynyl)benzene 77 4-(5-Hydroxypent-1-1-(5-Iodopent-1-ynyl)-4- 337.9 ynyl)trifluoromethyl-benzenetrifluoromethylbenzene 78 4-(5-Hydroxypent-1- 1-(5-Iodopent-1-ynyl)-4-ynyl)trifluoromethoxy- trifluoromethoxy-benzene benzene 79[3-Methyl-4-(5-hydroxypent- [4-(5-Iodopent-1-ynyl)-3- 399.91-ynyl)-phenyl]carbamic methylphenyl]carbamic Acid tert-Butyl Ester Acidtert-Butyl Ester 80 N-tert-Butyl-3-(5- N-tert-Butyl-3-(5-iodo-pent-383.8 hydroxypent-1-ynyl)-4- 1-ynyl)-4-methyl- methylbenzamide benzamide81 4-(5-hydroxypent-1- [4-(5-Iodopent-1-ynyl)- 385.9 ynyl)phenylcarbamicAcid phenyl]carbamic Acid tert- tert-Butyl Ester Butyl Ester 823-(5-Hydroxypent-1-ynyl)-4- 3-(5-Iodopent-1-ynyl)-4- methylbenzoic AcidMethyl methylbenzoic Acid Methyl Ester Ester 835-(3-Nitrophenyl)pent-4-yn- 1-(5-Iodopent-1-ynyl)-3- 315.8 1-olnitrobenzene 84 5-(4-Nitrophenyl)pent-4-yn- 1-(5-Iodopent-1-ynyl)-4-315.9 1-ol nitrobenzene 85 5-(4-tert-Butylphenyl) pent-4-1-tert-Butyl-4-(5-iodo-pent- 326.0 yn-1-ol 1-ynyl)benzene 865-(3-Chlorophenyl) pent-4- 1-Chloro-3-(5-iodopent-1- 304.0 yn-1-olynyl)benzene 87 6-(4-Chlorophenyl)hex-5-yn- 1-(4-Chlorophenyl)-6-iodo-1-ol 1-hexyne 88 11-(4-Chlorophenyl)-undec- 1-(4-Chlorophenyl)-11-10-yn-1-ol iodo-1-undecyne

EXAMPLE 89 1-(3-Bromo-1-propynyl)-4-phenoxybenzene

A solution of 3-(4-phenoxyphenyl)prop-2-yn-1-ol of Example 51 (415 mg,1.85 mmol), triphenylphosphine (514 mg, 1.96 mmol), carbon tetrabromide(650 mg, 1.96 mmol) in THF (3 ml) was stirred at room temperature for 3days. Evaporation of the solution, and chromatography of the residuegave the title compound as a brown oil: NMR (CDCl₃) δ 4.16 (s, 2H), 6.91(d, J=2.1, 1H), 6.93 (d, J=2.1, 1H), 7.01 (d, J=0.93, 1H), 7.04 (d,J=1.14, 1H), 7.12-7.17 (m, 1H), 7.36 (d, J=0.75, 1H), 7.39 (d, J=1.98,2H), 7.42 (d, J=2.64, 1H). MS m/z 288 (M+1 calcd. for C₁₅H₁₁BrO287.155).

In the manner described in Example 89, above, the following alcoholswere converted to the corresponding bromides of Examples 90-91:

Mass EX. No. ALCOHOL PRODUCT spectrum 90 3-Thiophene-2-ylprop-2-2-(3-Bromoprop-1-ynyl)-thiophene 201.9 (M + H) yn-1-ol 913-Biphenyl-4-ylprop-2-yn- 4-(3-Bromoprop-1-ynyl)-   270 (M − H) 1-olbiphenyl

EXAMPLE 925-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine-2,4-dione

To a solution of 5-(4-methoxyphenyl-4-sulfanyl)thiazolidine-2,4-dione[U.S. Pat. No. 5,605,918; February 1997; Wrobel, et al.](1.00 g, 3.92mmol)in THF (40 ml) was added NaH (0.34 g, 8.62 mmol)at 0° C. andstirring was continued for 30 minutes. To this was added a solution of1-(4-chlorophenyl)-5-iodo-1-pentyne (1.25 g, 4.12 mmol)in 3 ml of THF.This was then stirred at room temperature for 18 hours, and thenquenched in water. The resultant oil was chromatographed on silica gelusing hexane:ethyl acetate (4:1) to give the title compound as a paleyellow solid, m.p. 106-109° C.

In the manner described in Example 92 immediately above, the appropriatesubstituted alkyl iodide was reacted with a substitutedphenylthiazolidinedione to give the following compounds of Examples 93-96:

EXAMPLE 935-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine-2,4-dione

MS m/z 444.2 (calcd for C₂₂H₂₀ClNO₃S₂ 445.99).

EXAMPLE 945-[11-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxy-phenylsulfanyl)-thiazolidine-2,4-dione

mp 54-56° C., MS m/z 514.0 (calcd. for C₂₇H₃₀ClNO₃516.1).

EXAMPLE 955-(4-Methoxyphenylsulfanyl)-5-(5-thiophen-2-yl-pent-4-ynyl)-thiazolidine-2,4-dione

This was used in the next step without further purification.

EXAMPLE 965-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-fluorophenylsulfanyl)-thiazolidine-2,4-dione

This was used in the next step without further purification.

EXAMPLE 975-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione

To a solution of5-[5-(4-Chlorphenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine-2,4-dioneof Example 92 above,(0.87 g, 2.0 mMol) in glacial acetic acid (30 ml)at60° C was added 30% hydrogen peroxide (0.82 ml, 8.0 mmol). After 30minutes the reaction mixture was evaporated and the residue wassubjected to chromatography to give the title compound, MS (M−H) m/z462.0 (calcd. For C₂₁H₁₈ClNO₅S₂463.96).

EXAMPLE 985-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione

5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine-2,4-dione(0.30 g, 0.81 mmol) and isobutyraldehyde (0.37 ml, 4.04 mmol) weredissolved in acetonitrile (40 ml). Oxygen was bubbled through thissolution for 18 hours, and then the solution was evaporated and theresidue was subjected to chromatography on silica gel (hexane-ethylacetate, 1:1) to give 0.108 g, 28% yield of the title compound, mp145-148° C., MS m/z 476.0.

EXAMPLE 995-[11-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione

5-[11-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine-2,4-dionewas converted to the title compound using the procedure of Example 98immediately above, mp 114-121° C.

EXAMPLE 1005-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione

To a solution of 5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione[U.S. Pat. No. 5,605,918; February 1997; Wrobel, et al.]((2.74 g, 9.5mMol) in DMF (50 ml) was added sodium hexamethyldisilazane (1.0 Msolution in THF-19.0 ml, 19.0 mmol) at room temperature, under nitrogen,and this was stirred for 15 minutes. To this was added1-(4-chlorophenyl)-5-iodo-1-pentyne (2.70 g, 9.5 mmol) over 5 minutes,and this solution was stirred overnight at room temperature. Thereaction mixture was quenched in water, and the solid that was obtainedwas recrystallized from methanol to give 1.59 g of the title compound ascolorless crystals, m.p. 172-174°; NMR (CDCl₃) δ1.59 (m, 1H); 2.0(m,1H); 2.36 (dq (doublet of quartets?), 1H); 2.5 (t, 2H); 2.67 (dq, 1H);3.88 (s, 3H); 7.0 (d, 2H); 7.26 (s, 4H) 7.86 (d, 2H) In a manneressentially that of Example 100, the following products of Examples101-171 were obtained by alkylation of an arylthiazolidine-2,4-dionewith the appropriate iodo or bromo compound. All structures wereverified by NMR and gave spectra consistent with that shown in Example100:

Ex. melting mass spectrum No. Product point ° C. m/z (M − H) 1015-[5-(2-Chlorophenyl)pent-4-ynyl]-5-(4- 133-135 463.0methoxybenzenesulfonyl)-thiazolidine-2,4- dione 1025-[5-(3-Chlorophenyl)pent-4-ynyl]-5-(4- 134-136 463.0methoxybenzenesulfonyl)-thiazolidine-2,4- dione 1035-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(p- 176-177 447.0tolylsulfonyl)-thiazolidine-2,4-dione 1045-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4- 157-159 558.8iodobenzenesulfonyl)-thiazolidine-2,4-dione 1055-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4- 450.9fluorobenzenesulfonyl)-thiazolidine-2,4- dione 1065-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4- 193-194 525.0phenoxybenzenesulfonyl)-thiazolidine-2,4- dione 1075-[5-(4-Chlorophenyl)pent-4-ynyl]-5- 150-153 483.0(naphthalene-2-sulfonyl)-thiazolidine-2,4- dione 108N-(4-{5-[5-(4-Chlorophenyl)pent-4-ynyl]-2,4- 232 490.0dioxothiazolidine-5- decomp. sulfonyl}phenyl)acetamide 1095-[5-(4-Chlorophenyl)pent-4-ynyl]-5- pale 484.0(quinoline-8-sulfonyl)-thiazolidine-2,4-dione yellow solid 1105-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4- Tan solid 477.9nitrobenzenesulfonyl)-thiazolidine-2,4-dione 1115-(4-Benzyloxybenzenesulfonyl)-5-[5-(4- 181-184 539.0chlorophenyl)pent-4-ynyl]-thiazolidine-2,4- dione 1125-(4-Butoxybenzenesulfonyl)-5-[5-(4- 116-118 505.0chlorophenyl)-pent-4-ynyl]-thiazolidine-2,4- dione 1135-[5-(4-Chlorophenyl)pent-4-ynyl]-5- 172-174 483.0(naphthalene-1-sulfonyl)-thiazolidine-2,4- dione 1145-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4- 124-126 497.4methoxy-benzenesulfonyl)-thiazolidine-2,4- dione 1155-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4- yellow 593.3iodobenzenesulfonyl)-thiazolidine-2,4-dione amorphous solid 1165-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-[4- 179-180 560.5(pyridin-4-yloxy)benz- decomp. enesulfonyl]-thiazolidine-2,4-dione 1175-[5-(2,4-Dichlorophenyl)pent-4-ynyl]-5-(4- 129-133 497.4methoxybenzenesulfonyl)-thiazolidine-2,4- dione 1185-(4-Methoxybenzenesulfonyl)-5-[5-(3- 126-130 473.5nitrophenyl)pent-4-ynyl]-thiazolidine-2,4- dione 1195-[5-(3-Nitrophenyl)pent-4-ynyl]-5-(4- 190-191 535.6phenoxybenzenesulfonyl)-thiazolidine-2,4- dione 1205-(4-Iodobenzenesulfonyl)-5-[5-(4- 205-207 569.4nitrophenyl)pent-4-ynyl]-thiazolidine-2,4- dione 121 5-(4-Methoxybenzenesulfonyl)-5-[5-(4- 156-158 473.5nitrophenyl)pent-4-ynyl]-thiazolidine-2,4- dione 122 5-(4-Methoxybenzenesulfonyl)-5-[5-(2- yellow oil 487.5 methyl-5-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dione 123 5-(4-Methoxybenzenesulfonyl)-5-[5-(2-orange 503.5 methoxy-5-nitrophenyl)pent-4- solidynyl]-thiazolidine-2,4-dione 1245-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5- 203-204 549.6(4-phenoxybenzenesulfonyl-thiazolidine- 2,4-dione 1255-(4-Iodobenzenesulfonyl)-5-[5-(2-methyl-5- 188-190 583.4nitrophenyl)pent-4-ynyl]-thiazolidine-2,4- dione 1265-[5-(2-Methyl-5-nitrophenyl)-pent-4-ynyl]- 168-172 507.65-(naphthalene-1-sulfonyl)-thiazolidine-2,4- dione 1275-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5- 197-200 507.6(naphthalene-2-sulfonyl)-thiazolidine-2,4- dione 1285-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5- 199 572.6[4-(pyridin-4-yloxy)- decomp. benzenesulfonyl]-thiazolidine- 2,4-dione129 5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5- 210-212 549.6(4-phenoxybenzenesulfonyl)-thiazolidine- 2,4-dione 1305-(4-Methoxybenzenesulfonyl)-5-[5-(2- yellow 487.5methyl-4-nitrophenyl)-pent-4-ynyl]- glass thiazolidine-2,4-dione 1315-(4-Iodobenzenesulfonyl)-5-[5-(2-methyl-4- 150-152 657.5nitrophenyl)pent-4-ynyl]-thiazolidine-2,4- dione 1325-(4-Methoxybenzenesulfonyl)-5-[5-(2- yellow 503.5methoxy-4-nitrophenyl)pent-4- gum ynyl]-thiazolidine-2,4-dione 1335-[5-(3-Fluoro-5-nitrophenyl)pent-4-ynyl]-5- white 491.5(4-methoxybenzene-sulfonyl)-thiazolidine- solid 2,4-dione 1345-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4- 129-130 552.4iodobenzenesulfonyl)-thiazolidine-2,4-dione 1355-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4- 149-150 456.6methoxybenzenesulfonyl)-thiazolidine-2,4- dione 1365-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4- 155-156 456.6methoxybenzenesulfonyl)-thiazolidine-2,4- dione 1375-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4- 153-154 552.4iodobenzenesulfonyl)-thiazolidine-2,4-dione 1385-[5-(5-Chloro-2-methylphenyl)pent-4- 121-122 477.0ynyl]-5-(4-methoxybenzene- sulfonyl)thiazolidine-2,4-dione 1395-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]- 196 549.05-(4-trifluoromethoxybenzene- decomp. sulfonyl)thiazolidine-2,4-dione140 5-[5-(4-Chloro-2-methylphenyl)pent-4- 197 559.9ynyl]-5-(4-trifluoromethoxy- decomp.benzenesulfonyl)thiazolidine-2,4-dione 1415-[5-(4-Chloro-2-methylphenyl)-pent-4- 93-99 591.4ynyl]-5-(4-iodobenzene-sulfonyl)- thiazolidine-2,4-dione 1425-[5-(4-Chloro-2-methylphenyl) pent-4- yellow 477.0ynyl]-5-(4-methoxybenzene-sulfonyl)- foam thiazolidine-2,4-dione 1435-[5-(4-Bromo-2-methy-phenyl)pent-4- white 540.0ynyl]-5-(4-methoxybenzene-sulfonyl)- foam thiazolidine-2,4-dione 1445-[5-(4-Bromo-2-methylphenyl)pent-4-ynyl]- 146-147 617.35-(4-iodobenzenesulfonyl)-thiazolidine-2,4- dione 145(4-{5-[5-(4-Methoxybenzensulfonyl)-2,4- yellow 543.7dioxothiazolidin-5-yl]pent-1- solid ynyl}phenyl)carbamic Acid tert-ButylEster 146 (3-Chloro-4-{5-[5-(4-methoxybenzene yellow oil 578.1sulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1- ynyl}phenyl)carbamic Acidtert-Butyl Ester 147 N-tert-Butyl-3-{5-[5-(4-iodo- white 637.5benzenesulfonyl)-2,4-dioxothiazol-idin-5- powderyl]-pent-1-ynyl}-4-methylbenzamide 148(3-{5-[5-(4-Iodobenzenesulfonyl)-2,4- 172-175 653.5dioxothiazolidin-5-yl]-pent-1-ynyl}-4- methylphenyl)carbamic Acidtert-Butyl Ester 149 (4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- yellow557.7 dioxo-thiazolidin-5-yl]pent-1-ynyl}-3- solid methylphenyl)carbamicAcid tert-Butyl Ester 150 (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-116-118 557.7 dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid tert-Butyl Ester 151(4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- tan solid 611.6dioxothiazolidin-5-yl]pent-1-ynyl}-3- trifluoromethylphenyl)-carbamicAcid tert- Butyl Ester 152 N-tert-Butyl-3-{5-[5-(4-methoxy- 205-208541.7 benzenesulfonyl)-2,4-dioxothiazol-idin-5-yl]pent-1-ynyl}-4-methyl-benzamide 1535-(4-Methoxybenzenesulfonyl)-5-[5-(4- 160-163 496.5trifluoromethylphenyl)pent-4- ynyl]-thiazolidine-2,4-dione 1545-(4-Methoxybenzenesulfonyl)-5-[5-(4- 120-123 512.5trifluoromethoxyphenyl)pent-4- ynyl]-thiazolidine-2,4-dione 1553-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 119-121 500.6dioxo-thiazolidin-5-yl]-pent-1-ynyl}-4- methylbenzoic Acid Methyl Ester156 5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5-(4- yellow oil 484.6methoxybenzenesulfonyl)-thiazolidine-2,4- dione 1575-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5- 134-138 468.6(toluene-4-sulfonyl)-thiazolidine-2,4-dione 1584-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 174-178 453.5dioxo-thiazolidin-5-yl]pent-1- ynyl}benzonitrile 1595-[5-(4-Methanesulfonylphenyl)-pent-4- 190-193 490.6ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4- dione 1604-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 128-130 500.6dioxothiazolidin-5-yl]pent-1-ynyl}-3- methylbenzoic Acid Methyl Ester161 5-(4-Methoxybenzenesulfonyl)-5-[5-(4- 206-207 493.6pyrrol-1-yl-phenyl)pent-4-ynyl]-thiazolidine- 2,4-dione 1625-(4-Iodo-benzenesulfonyl)-5-[5-(4-pyrrol-1- 194-195 589.5yl-phenyl)pent-4-ynyl]-thiazolidine-2,4-dione 1635-[5-(4-Pyrrol-1-ylphenyl)pent-4-ynyl]-5-(4- 204-206 547.6trifluoromethoxybenzenesulfonyl)- thiazolidine-2,4-dione 1645-(3-Methoxybenzenesulfonyl)-5-(5- 133-135 434.5thiophen-2-yl-pent-4-ynyl)-thiazolidine-2,4- dione 1655-(4-Methylphenylsulfonyl)-5-(5-thiophen-2- brown 390.5yl-pent-4-ynyl)-thiazolidine-2,4-dione gum 1665-(4-Methoxybenzenesulfonyl)-5-(5- 60-66 434.5thiophen-2-yl-pent-4-ynyl)-thiazolidine-2,4- dione 1675-(4-Methoxybenzenesulfonyl)-5-(3-pyridin- tan solid 403.03-ylprop-2-ynyl)-thiazolidine-2,4-dione 1685-(3-Thiophen-2-yl-prop-2-ynyl)-5-(toluene- brown 392.14-sulfonyl)-thiazolidine-2,4-dione solid 1695-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(toluene- 179-180 4624-sulfonyl)-thiazolidine-2,4-dione 1705-[3-(4-Phenoxyphenyl)prop-2-ynyl]-5- 64-66 478.1(toluene-4-sulfonyl)-thiazolidine-2,4-dione 1715-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(4- orangemethoxybenzenesulfonyl)-thiazolidine-2,4- oil dione

EXAMPLE 172 5-Pent-4-ynyl-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione

In the manner of Example 100 above, 5-iodo-1-pentyne is created with5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione to give the titlecompound, mp 226° C., THEORY: C,53.4, H, 4.48, N, 4.15 FOUND: C, 53.3,H, 4.58, N, 4.13.

EXAMPLE 1735-Pyridin-3-yl-pent-4-ynyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione

A solution of5-pent-4-ynyl-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione(1.0 mmol),4-pentyn-1-ol (1.0 mmol), bistriphenylphosphine(Pd II) chloride (0.20mmol), and copper(I) iodide (0.10 mmol), in 50 ml of diethylamine wasstirred under nitrogen for three days. This was diluted withdichloromethane and the product was purified by chromatography to givethe title compound as a light beige solid, mp 173-176° C., THEORY: C,57.95, H, 4.38 N, 6.76. FOUND: C, 57.68, H, 4.35, N, 6.70.

EXAMPLE 1745-[5-(5-Amino-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione

(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicacid, tert-butyl ester was subjected to acid hydrolysis which gave thetitle compound as a brown solid, MS m/Z 458.9 (calcd. For C₂₂H₂₂N₂O₅S₂458.56).

EXAMPLE 175 to 194

The following general procedure was used to prepare the compounds ofExamples 175 to 194. A solution of 1.15 g (2.5 mmol)of compound ofExample 174, above, in a total of 50 mL of dichloromethane was dividedequally in ten-20 mL scintillation vials. To each vessel was added 0.13mL (3 eq), of diisopropylethylamine, the appropriate acylating agent(1.2 eq, 0.3 mmol) and the mixture was allowed to react in an orbitalshaker overnight. Crude reaction mixtures were checked by Mass Spec forproduct. Once product formation was confirmed, the solutions wereevaporated to dryness under reduced pressure, taken up in 1 mL ofdichloromethane and purified via preparative HPLC. Each product fractionwas then evaporated to dryness in the vacuum apparatus, characterizedvia mas spectrometry.

Ex. Mass Spectrum No. Product (M − H) 175(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 591.1dioxothiazolidin-5-yl]pent-1-ynyl}-4- methylphenyl)carbamic Acid BenzylEster 176 (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 636.1dioxothiazolidin-5-yl]pent-1-ynyl}-4- methylphenyl)carbamic Acid4-Nitro-Benzyl Ester 177 (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 611.0dioxothiazolidin-5-yl]pent-1-ynyl}-4- methylphenyl)carbamic Acid4-Chloro-phenyl Ester 178 (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 515.0dioxothiazolidin-5-yl]pent-1-ynyl}-4- methylphenyl)carbamic Acid MethylEster 179 (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 543.1dioxothiazolidin-5-yl]pent-1-ynyl}-4- methylphenyl)carbamic AcidIsopropyl Ester 180 (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 571.1dioxothiazolidin-5-yl]pent-1-ynyl}-4- methylphenyl)carbamic AcidNeopentyl Ester 181 (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 557.1dioxothiazolidin-5-yl]pent-1-ynyl}-4- methylphenyl)carbamic Acid ButylEster 182 (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 557.1dioxothiazolidin-5-yl]pent-1-ynyl}-4- methylphenyl)carbamic AcidIsobutyl 183 N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3- 526.9thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2- methylpropanamide 184N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3- 555.0thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-3,3- dimethylbutanamide185 N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3- 541.0thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2,2- dimethylpropanamide186 N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3- 574.9thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2- phenylacetamide 187N-Benzyl-N′-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4- 589.9dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea 188N-(4-Methoxyphenyl)-N′-[3-(5-{5-[(4-methoxy 606.0phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea 189 N-(4-Chlorophenyl)-N′-[3-(5-{5-[(4-methoxy- 609.9phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea 190N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3- 590.0thiazolidin-5-yl}-1-pentynyl)-methylphenyl]-N′-(4- methylphenyl)urea 1914-Chloro-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo- 596.01,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide 1924-Methoxy-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4- 590.9dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4- methylphenyl]benzamide 193N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3- 636.9thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl][1,1′-biphenyl]-4-carboxamide 1944-(tert-Butyl)-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4- 617.0dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4- methylphenyl]benzamide

EXAMPLES 195 TO 213

The following general procedure was used to prepare the compounds ofExamples 195 to 213. A solution of 800 mg of each sulfone in 20 mLanhydrous DMF was distributed evenly among 4 vials (0.57-0.75 mmoleach). To each was added 2.1 eq 1.0M NaHMDS under a stream of N2 andreacted in an orbital shaker for 45 min. 1.05 equivalents of theappropriate alkylating agent was dissolved in 2 mL DMF and added underN2 to the above vials. The reactions were allowed to shake overnight atroom temp.

Each vial was diluted with 5 ml H₂O, acidified with 2NHCl, thenextracted with ethyl acetate. Crude extracts were evaporated to drynessunder reduced pressure in a vacuum apparatus, dissolved in 1 mL ofdichloromethane, then purified via preparative HPLC. The productfractions were collected, and evaporated to dryness under reducedpressure and analyzed via MS and NMR.

Mass Ex. Spectrum No. Product (M − H) 1955-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(5-chloro-2- 473.8thienyl)sulfonyl]-1,3-thiazolidine-2,4-dione 1965-[5-(4-Chlorophenyl)-4-pentynyl]-5-(2- 439.9thienylsulfonyl)-1,3-thiazolidine-2,4-dione 1975-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(3,4- 494.0dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione 1985-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[4-(4- 527.0pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidine-2,4- dione 1995-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[5-(2-pyridinyl)- 516.92-thienyl]sulfonyl}-1,3-thiazolidine-2,4-dione 2005-[(5-Chloro-2-thienyl)sulfonyl]-5-[5-(2,5- 509.8dichlorophenyl)-4-pentynyl]-1,3-thiazolidine-2,4- dione 2015-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-(2- 473.8thienylsulfonyl)-1,3-thiazolidine-2,4-dione 2025-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-[(3,4- 527.9dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione 2035-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[4-(4- 560.9pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidine-2,4- dione 2045-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[5-(2- 550.9pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidine-2,4- dione 205tert-Butyl 3-(5-{5-[(5-chloro-2-thienyl)-sulfonyl]-2,4- 569.0dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4- methylphenylcarbamate 206tert-Butyl 3-{5-[2,4-dioxo-5-(2-thienyl-sulfonyl)-1,3- 533.0thiazolidin-5-yl]-1-pentyn-yl}-4- methylphenylcarbamate 207 tert-Butyl3-(5-{5-[(3,4-dimethoxy- phenyl)sulfonyl]- 587.12,4-dioxo-1,3-thiazol-idin-5-yl}-1-pentynyl)-4- methylphenylcarbamate208 tert-Butyl 3-[5-(2,4-dioxo-5-{[4-(4- 620.1pyridinyloxy)phenyl]sulfonyl}-1,3-thiazol-idin-5-yl)-1-pentynyl]-4-methylphenylcarbamate 209 tert-Butyl3-[5-(2,4-dioxo-5-{[5-(2-pyrid-inyl)-2- 610.0thienyl]sulfonyl}-1,3-thiazol-idin-5-yl)-1-pentynyl]-4-methylphenylcarbamate 210N-(tert-Butyl)-3-(5-{5-[(5-chloro-2-thienyl)sulfonyl]- 553.02,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4- methylbenzamide 211N-(tert-Butyl)-3-{5-[2,4-dioxo-5-(2-thienylsulfonyl)- 517.11,3-thiazolidin-5-yl]-1-pentynyl}-4-methylbenzamide 212N-(tert-Butyl)-3-(5-{5-[(3,4- 571.1dimethoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylbenzamide 213N-(tert-Butyl)-3-[5-(2,4-dioxo-5-{[5-(2-pyridinyl)-2- 594.0thienyl]sulfonyl}-1,3- thiazolidin-5-yl)-1-pentynyl]-4-methylbenzamide

EXAMPLE 2144-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-3-methylbenzoicAcid

To a solution of4-{5-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}-3-methylbenzoicacid methyl ester (Example 160)(0.29 g, 0.536 mmol) in THF (30 ml plussufficient methanol to dissolve the substrate) was added lithiumhydroxide (0.75 ml of 1.0M in water), and this solution was stirred atroom temperature for 3 days. Dilution with water and acidification gavea solid which was crystallized from hexane-ethyl acetate to give thetitle compound as a light yellow solid mp 182-184° C. THEORY: C, 56.66,H, 4.34, N, 2.87. FOUND: C, 56.39, H, 4.60, N, 2.80.

EXAMPLE 215N-(4-Chlorobenzyl)-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-4-yl]propionamide

To a solution of 5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione[U.S. Pat. No. 5,605,918; February 1997; Wrobel, et al.]((5.0 g, 17.4mmol) in 150 ml of DMF was added sodium bistrimethylsilylamide (36.6 mlof 1.0 M solution in THF) and this solution was stirred for 15 minutes.To this was added methyl 3-iodopropionate (17.4 mmol) and this solutionwas stirred for three hours and then was subjected to an aqueous workup.The product was chromatographed (silica gel, hexane-ethylacetate-dichloromethane, 1:1:1) to give methyl3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidin-4-yl]propionate,4.48 g. This was hydrolyzed with lithium hydroxide, THF, methanol togive3-[5-(4-methoxybenzene-sulfonyl)-2,4-dioxothiazolidin-4-yl]propionicacid which was used without further purification in the followingprocedure:

To a solution of the above acid (0.4 g, 1.1 mmol) in 15 ml ofdichloromethane plus 2 ml of DMF was added 4-chlorobenzylamine (0.2 ml,1.67 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.255 g, 1.33 mmol), and this was stirred at roomtemperature for 18 hours. Aqueous workup, and chromatography (silicagel, chloroform-methanol-5%) gave the title compound as a colorlesssolid, mp 90° C. and decomposes over wide range.

EXAMPLE 216N-[2-(4-Chlorophenyl)ethyl]-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]propionamide

In a like procedure to Example 215, above, 4-chlorophenethylamine gavethe title compound as a white powder, mp 189° C. with decomposition.

EXAMPLE 2175-[(4Z)-5-(4-Chloro-phenyl)pent-4-enyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione

A sample of5-[5-(4-chlorophenyl)pent-4-ynyl]-5-(p-tolylsulfonyl)-thiazolidine-2,4-dione(Example 103) was hydrogenated in the presence of Lindlars catalyst inethanol to give the title compound as a white solid, NMR (CDCl₃) δ 2.47(s, 3H), 5.57 (apparent d of triplets, J=7.3, 11.6 Hz, 1H), 6.42 (br d,J=11.6 Hz, 1H) MS m/Z 499.0495 (M⁺ calcd. for C₂₁H₂₀ClNO₄S₂ 499.0523).

EXAMPLE 2185-[(4E)-5-(4-Chlorophenyl)pent-4-enyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione

A mixture of 4-pentyn-1-ol, 1.05 eq tri-n-butyltinhydride and acatalytic amount of 1,1′-azobis(cyclohexanecarbonitrile), was heated to55° C. overnight. The mixture was cooled, then purified on silica gelusing 6:1 hex: EtOAc to 4:1 as eluent to give 86% yield oftri-n-butyl(4-pentenol)-5-ylstannane as a clear liquid which containedboth cis and trans isomers. Then, 4-chloroiodobenzene (1.0 equiv.) wasdissolved in anhydrous DMF under a nitrogen atmosphere.Tri-n-butyl(4-pentenol)-5-ylstannane(1.0 equiv.) was added, followed bytetrakis-triphenylphosphinePd(0)(0.1 equiv.) and Cul (0.75 equiv.). Thereaction was stirred at room temperature overnight. The reaction wasdiluted with ether, filtered through a small pad of celite and an excessof saturated aqueous NH₄Cl was added, and this was stirred for 1 h.Combined organics were washed with brine, and dried over MgSO₄ to afforda tan semi-solid. This was purified using silica and 4:1 Hex: MeOtBu to1:1. Obtained three cuts: 20% pure ‘Z’ isomer, 26% mix, 19.6% ‘E’ isomer(desired trans isomer) which was a light tan low melting solid.

A solution of imidazole (1.3 equiv.) and triphenylphosphine (1.3 equiv.)in acetonitrile-ether was cooled to 0° C. Iodine (1.4 equiv.) was addedin three portions, and the solution was then allowed to warm to roomtemp overnight.

The mixture was dissolved in methylene chloride, and directlypreadsorbed onto silica gel and purified using 25:1 Hexanes: EtOAc aseluent to give the iodo-compound as a clear liquid. In an oven-driedround bottom flask under nitrogen was dissolved the sulfone in anhydrousDMF. Sodium hexamethyldisilazane (1.0 M solution in THF-2.1 equiv.) wasadded dropwise at room temperature and allowed to react at room temp forone hour. The iodide (1.1 equiv.) was dissolved in DMF, then added inone portion to the above solution., and allowed to react overnight.

The reaction was diluted with water, acidified to approx. pH 2 using 2NHCl, extracted with ethyl acetate (3×), combined organics, washed withbrine, dried over MgSO₄ and concentrated to afford an oil which waspurified on silica gel using 1:2:1 CH₂Cl₂: hex: EtOAc to afford thetitle compound, 36% as an off-white solid, mp 182-184° C., E-doublebond—NMR (CDCl₃) δ6.18 (td, 1H, J=22.5 Hz), 6.31 (d, 1H, J=22.5 Hz).

EXAMPLE 2195-[3-(4-Chlorophenyl)propyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione

A sample of5-[3-(4-Chlorophenyl)prop-2-ynyl]-5-(4-methoxy-benzenesulfonyl)thiazolidine-2,4-dione(U.S. Pat. No. 5,605,918; February 1997; Wrobel, et al.) washydrogenated in the presence of palladium on charcoal (10%) in methanolplus 2% water to give the title compound as a colorless glass, NMR(CDCl₃) δ1.57 (m, 1H); 1.97(m, 1H); 2.20 (triplet of doublet), 1H); 2.45(m, 1H); 2.61 (q, 2H); 3.92 (s, 3H); 7.0 (dd, 4H); 7.26 (d, 2H) 7.98 (d,2H).

EXAMPLE 2205-[5-(3-Aminophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione

A sample of5-(4-methoxybenzenesulfonyl)-5-[5-(3-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dioneof Example 118 was reduced with iron in acetic acid to give the titlecompound as crystals, m.p. 135-138° C.

EXAMPLE 2215-(3-Phenylallyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione

Alkylation with cinnamyl bromide (222 mg, 1.13 mmol) of5-(4-methylphenylsulfonyl)-thiazolidine-2,4-dione (271 mg, 1.00 mmol)following the procedure in example 3 yield 32 mg (8%) of light yellowoil which was identified as5-(3-Phenylallyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione: NMR(CDCl₃) δ 2.49 (s, 3H), 3.06-3.13 (m, 1H), 3.34-3.42 (m, 1H), 6.01-6.11(m, 1H), 6.60 (d, J=15.69, 1H), 7.26-7.31 (m, 5H), 7.42 (d, J=8.13, 2H),7.85 (d, J=8.34, 2H) MS m/z 388.1 (M+H cald. for C₁₉H₁₇NO₄S₂ 387.48)

EXAMPLE 222 Enantiomer of(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid tert-Butyl Ester (less polar)

The compound of Example 150 was chromatographed on a chiral column withhexane-ethanol 4:1 to give a less polar enantiomer, retention time14.5-16 min.

EXAMPLE 223 Enantiomer of(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid tert-Butyl Ester (more polar)

Continued chromatography of the compounds in Example 223 gave a morepolar enantiomer, retention time 19-21 min.

EXAMPLE 224 5-(4-methoxyphenyl-4-sulfinyl)-thiazolidine-2,4-dione

5-(4-methoxyphenyl-4-sulfanyl)-thiazolidine-2,4-dione [U.S. Pat. No.5,605,918; February 1997; Wrobel, et al.] was oxidized as described forExample 98 to give the title compound: NMR (CDCl₃) δ3.80 (S, 3H), 5.77(S, 1H), 7.04 (d, 2H), 7.62 (d, 2H).

EXAMPLE 2255-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfinyl)-thiazolidine-2,4-dione

By the method of Example 92, the compound of Example 224, above, isconverted to the title compound.

EXAMPLES 226-233

In the isolation of products of Examples 175 to 194 the N-3-acylatedproducts of Examples 227 to 234 were isolated and the structures wereverified by mass spectrometry and NMR:

Ex. No. Compound 226 Benzyl 5-[5-(5-{[(benzyloxy)carbonyl]-amino}-2-methylphenyl)pent-4-ynyl]-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine- 3-carboxylate 2274-Nitrobenzyl 5-[(4-methoxyphenyl)sulfonyl]-5-{5-[2-methyl-5-({[(4-nitro benzyl)oxy]carbonyl}amino)phenyl]pent-4-ynyl}-2,4-dioxo-1,3-thiazolidine-3- carboxylate 228 Methyl5-(5-{5-[(methoxycarbonyl)amino]-2- methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine- 3-carboxylate 229Isopropyl 5-(5-{5-[(isopropoxycarbonyl)-amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine- 3-carboxylate 230Neopentyl 5-[(4-methoxyphenyl)sulfonyl]-5-[5-(2-methyl-5-{[(neopentyloxy)carbonyl]-amino}phenyl)pent-4-ynyl]-2,4-dioxo-1,3- thiazolidine-3-carboxylate 231Butyl 5-(5-{5-[(butoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxy-phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3- carboxylate 232 Isobutyl5-(5-{5-[(isobutoxycarbonyl)-amino]-2- methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine- 3-carboxylate

EXAMPLE 2335-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(3-imidazol-1-yl-propyl)-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione

The compound of Example 97 is reacted with 1,3-dibromopropane andpotassium carbonate in DMF to give5-[5-(4-chlorophenyl)pent-4-ynyl]-3-(3-bromopropyl)-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,and this is reacted with imidazole, sodium salt in DMF, and in thepresence of a catalytic amount of potassium iodide to give the titlecompound as a light tan solid, mp 111-113° C.

EXAMPLE 2345-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-3-methyl-thiazolidine-2,4-dione

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione(Example 100) is reated with sodium hydride in DMF, followed by methyliodide to give the title compound as colorless crystals, mp 113-11 5° C.

EXAMPLE 2353-(2,4-diethoxybenzyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione

5-(Toluene-4-sulfonyl)-thiazolidine-2,4-dione[U.S. Pat No. 5,605,918;February 1997; Wrobel, et al.] was reacted with 2,4-diethoxybenzylalcohol in the presence of triphenylphosphine and diethyldiazodicarboxylate to give the title compound as colorless crystals, mp121-123° C.

EXAMPLE 2365-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(2,4-diethoxybenzyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione

The product of Example 237 is reacted with sodium hexamethyldisilazanein DMF, followed by the addition of1-chloro-4-(5-iodopent-1-ynyl)-benzene to give the title compound ascolorless crystals, mp 151-153° C.

EXAMPLE 2375-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-3-(4-nitrobenzyl)-thiazolidine-2,4-dione

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiazolidine-2,4-dioneis reacted with 4-nitrobenzyl bromide and potassium carbonate in DMF togive the title compound as a light tan solid, mp 172-175° C.

EXAMPLE 2385-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidine-3-carboxylicacid 2-methoxy ethyl ester

5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dioneis reacted with (2-methoxyethoxy)chloroformate and diisopropylethylaminein methylene chloride to give the title compound as a solid, MS m/z599.8 (calcd. for C₂₅H₂₃Cl₂NO₈S₂ 600.5).

What is claimed is:
 1. A compound of Formula (I) represented by thestructure:

wherein: Ar is 1-naphthyl, 2-naphthyl, 8-quinolinyl, 2-thienyl,5-chloro-2-thienyl, 5-(2-pyridyl)-2-thienyl, 2-pyridinyl, substituted2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl, 2-pyrimidinyl,2-benzoxazolyl, 2-benzthiazolyl, 2-benzimidazolyl, 2-furanyl,2-benzo-[b]-furanyl, 2-benzo-[b]-thienyl or a moiety of the formula:

R₁ is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms,4-pyridyloxy, azido, nitro,acetamido, trifluoromethoxy, phenoxy, or benzyloxy; R₂ is hydrogen,fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbon atoms, alkoxy of 1to 6 carbon atoms, trifluoromethoxy, phenoxy, or benzyloxy; m is 0, 1 or2; R₆ is hydrogen, alkyl of 1 to 6 carbon atoms, benzyl, substitutedbenzyl, imidazolylpropyl, or —CO₂Y; Y is 2-methoxyethyl, alkyl is 1 to 6carbon atoms, benzyl, or substituted benzyl; W is

 E— and Z——CH═CH—, —CONH—, —CONHCH₂—, CONHCH₂CH₂— or —CH₂—CH₂—; n is aninteger of 1 to 9; Ar′ is thienyl, pyridinyl or a moiety of the formula:

R₃, R₄, R₅, are independently selected from hydrogen, alkoxy of 1 to 6carbon atoms, alkyl of 1 to 6 carbon atoms, fluoro, bromo, chloro, iodo,nitro, amino, hydroxy, azido, cyano, phenyl, phenoxy, trifluoromethyl,trifluoromethoxy, methanesulphonyl, 1-pyrrolyl, —CO₂R₇, —CONHR₈,—CH₂CONHR₉, —NHCO₂R₁₀, —NHCOR₁₁, and —NHCONHR₁₂; R₇ is selected from H,and alkyl of 1 to 6 carbon atoms, R₈ is selected from H, and alkyl of 1to 6 carbon atoms; R₉ is selected from H, and alkyl of 1 to 6 carbonatoms; R₁₀ is selected from alkyl of 1 to 6 carbon atoms, benzyl,nitrobenzyl, and chlorophenyl; R₁₁ is selected from alkyl of 1 to 6carbon atoms, benzyl, phenyl, halophenyl, alkyl(1 to 6 carbonatoms)phenyl, alkoxy(1 to 6 carbon atoms)phenyl, and biphenyl; R₁₂ isbenzyl, alkyl of 1 to 6 carbon atoms, alkoxy(1 to 6 carbon atoms)phenyl,halophenyl, and alkyl(1 to 6 carbon atoms)phenyl; provided when W is

 then n is other than 2; further provided that when n is 1, m is 0 or 2,R₆ is H and W is

 then: Ar is not phenyl, 2-naphthyl, alkyl substituted phenyl, alkoxysubstituted phenyl, halogen substituted phenyl, 2-pyridinyl, substituted2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl, 2-pyrimidinyl,2-benzoxazolyl, 2-benzthiazolyl, 2-benzimidazolyl, 2-furanyl,2-benzo-[b]-furanyl, 2-thienyl, or 2-benzo-[b]-thienyl; and Ar′ is notphenyl, alkyl substituted phenyl, perfluoroalkyl (mono or di)substitutedphenyl, halogen substituted phenyl, alkoxy substituted phenyl,perfluoroalkoxy substituted phenyl or alkylthio substituted phenyl; orpharmaceutically acceptable salts thereof.
 2. A compound according toclaim 1 wherein R₆ is hydrogen, n is 3, m is 2, W is

or a pharmaceutically acceptable salt thereof.
 3. A compound accordingto claim 1 wherein R₆ is hydrogen, n is 3, m is 2, W is

Ar is a moiety of the formula:

or a pharmaceutically acceptable salt thereof.
 4. A compound accordingto claim 1 wherein R₆ is hydrogen, n is 3, m is 2, W is

Ar is a moiety of the formula:

Ar′ is a moiety of the formula:

or a pharmaceutically acceptable salt thereof.
 5. A compound accordingto claim 1 wherein R₆ is hydrogen, n is 3, m is 2, W is

Ar is a moiety of the formula:

Ar′ is thienyl or pyridinyl or a pharmaceutically acceptable saltthereof.
 6. A compound according to claim 1 wherein R₆ is hydrogen, n is3-6, m is 2, W is

or a pharmaceutically acceptable salt thereof.
 7. A compound accordingto claim 1 wherein R₆ is hydrogen, n is 3-6, m is 2, W is

Ar is a moiety of the formula:

or a pharmaceutically acceptable salt thereof.
 8. A compound accordingto claim 1 wherein R₆ is hydrogen, n is 3-6, m is 2, W is

Ar is a moiety of the formula:

Ar′ is a moiety of the formula:

or a pharmaceutically acceptable salt thereof.
 9. A compound accordingto claim 1 wherein R₆ is hydrogen, n is 3-6, m is 2, W is

Ar is a moiety of the formula:

Ar′ is thienyl or pyridinyl or a pharmaceutically acceptable saltthereof.
 10. A compound according to claim 1 wherein R₆ is hydrogen, nis 1, m is 2, W is

or a pharmaceutically acceptable salt thereof.
 11. A compound accordingto claim 1 wherein R₆ is hydrogen, n is 1, m is 2, W is

Ar is a moiety of the formula:

or a pharmaceutically acceptable salt thereof.
 12. A compound accordingto claim 1 wherein R₆ is hydrogen, n is 1, m is 2, W is

Ar is a moiety of the formula:

Ar′ is a moiety of the formula:

or a pharmaceutically acceptable salt thereof.
 13. A compound accordingto claim 1 wherein R₆ is hydrogen, n is 1, m is 2, W is

Ar is a moiety of the formula:

Ar′ is thienyl or pyridinyl or a pharmaceutically acceptable saltthereof.
 14. A compound according to claim 1 wherein m is 2, Ar isphenyl substituted in the 4-position by iodo, methoxy, trifluoromethoxy,4-pyridyloxy; Ar′ is phenyl substituted in the 2-position by chloro ormethyl, and in the 5-position by amino, chloro, a carbamic acid ester, asubstituted carboxamide group, or in the 4-position by nitro or acarbamic acid ester; W is an acetylenic group, and n is the integer 3 ora pharmaceutically acceptable salt thereof.
 15. The compound of claim 1selected from the group consisting of:5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine-2,4-dione,5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine-2,4-dione,5-[11-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine-2,4-dione,5-(4-Methoxyphenylsulfanyl)-5-(5-thiophen-2-yl-pent-4-ynyl)-thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-fluorophenylsulfanyl)-thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)thiazolidine-2,4-dione,5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfonyl)thiazolidine-2,4-dione,5-[11-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxyphenylsulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)thiazolidine-2,4-dione,5-[5-(2-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(3-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(p-tolylsulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-fluorobenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(naphthalene-2-sulfonyl)thiazolidine-2,4-dione,N-(4-{5-[5-(4-Chlorophenyl)pent-4-ynyl]-2,4-dioxothiazolidine-5-sulfonyl}phenyl)acetamide,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(quinoline-8-sulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-nitrobenzenesulfonyl)thiazolidine-2,4-dione,5-(4-Benzyloxybenzenesulfonyl)-5-[5-(4-chlorophenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-(4-Butoxybenzenesulfonyl)-5-[5-(4-chlorophenyl)-pent-4-ynyl]thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(naphthalene-1-sulfonyl)thiazolidine-2,4-dione,5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4-methoxy-benzenesulfonyl)thiazolidine-2,4-dione,5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-[4-(pyridin-4-yloxy)benzenesulfonyl]thiazolidine-2,4-dione,5-[5-(2,4-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-(4-Methoxybenzenesulfonyl)-5-[5-(3-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-[5-(3-Nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiazolidine-2,4-dione,5-(4-Iodobenzenesulfonyl)-5-[5-(4-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-(4-Methoxybenzenesulfonyl)-5-[5-(4-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methyl-5-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-5-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiazolidine-2,4-dione,5-(4-Iodobenzenesulfonyl)-5-[5-(2-methyl-5-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-[5-(2-Methyl-5-nitrophenyl)-pent-4-ynyl]-5-(naphthalene-1-sulfonyl)thiazolidine-2,4-dione,5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(naphthalene-2-sulfonyl)thiazolidine-2,4-dione,5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-[4-(pyridin-4-yloxy)benzenesulfonyl]-thiazolidine-2,4-dione,5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiazolidine-2,4-dione,5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)-pent-4-ynyl]thiazolidine-2,4-dione,5-(4-Iodobenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-4-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-[5-(3-Fluoro-5-nitrophenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)thiazolidine-2,4-dione,5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chloro-2-methylphenyl)-pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-Bromo-2-methy-phenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-Bromo-2-methylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,(4-{5-[5-(4-Methoxybenzensulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}phenyl)carbamicAcid tert-Butyl Ester, (3-Chloro-4-{5-[5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}phenyl)carbamic Acidtert-Butyl Ester,N-tert-Butyl-3-{5-[5-(4-iodo-benzenesulfonyl)-2,4-dioxothiazolidin-5-yl]-pent-1-ynyl}-4-methyl-benzamide,(3-{5-[5-(4-Iodobenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]-pent-1-ynyl}-4-methylphenyl)carbamicAcid tert-Butyl Ester,(4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}-3-methylphenyl)carbamicAcid tert-Butyl Ester,(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid tert-Butyl Ester,(4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-3-trifluoromethylphenyl)-carbamicAcid tert-Butyl Ester,N-tert-Butyl-3-{5-[5-(4-methoxy-benzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methyl-benzamide,5-(4-Methoxybenzenesulfonyl)-5-[5-(4-trifluoromethylphenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-(4-Methoxybenzenesulfonyl)-5-[5-(4-trifluoromethoxyphenyl)pent-4-ynyl]thiazolidine-2,4-dione,3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]-pent-1-ynyl}-4-methylbenzoicAcid Methyl Ester,5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}benzonitrile,5-[5-(4-Methanesulfonylphenyl)-pent-4-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,4-(5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl)-3-methylbenzoicAcid Methyl Ester,5-(4-Methoxybenzenesulfonyl)-5-[5-(4-pyrrol-1-yl-phenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-(4-Iodo-benzenesulfonyl)-5-[5-(4-pyrrol-1-yl-phenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-[5-(4-Pyrrol-1-ylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzenesulfonyl)thiazolidine-2,4-dione,5-(3-Methoxybenzenesulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiazolidine-2,4-dione,5-(4-Methylphenylsulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiazolidine-2,4-dione,5-(4-Methoxybenzenesulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiazolidine-2,4-dione,5-(4-Methoxybenzenesulfonyl)-5-(3-pyridin-3-ylprop-2-ynyl)thiazolidine-2,4-dione,5-(3-Thiophen-2-yl-prop-2-ynyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,5-[3-(4-Phenoxyphenyl)prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-(5-Pyridin-3-yl-pent-4-ynyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,5-[5-(5-Amino-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid Benzyl Ester,(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid 4-Nitro-Benzyl Ester,(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid 4-Chloro-phenyl Ester,(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid Methyl Ester,(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid Isopropyl Ester,(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid Neopentyl Ester,(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid Butyl Ester,(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid Isobutyl,N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2-methylpropanamide,N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-3,3-dimethylbutanamide,N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2,2-dimethylpropanamide,N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2-phenylacetamide,N-Benzyl-N′-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,N-(4-Methoxyphenyl)-N′-[3-(5-{5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,N-(4-Chlorophenyl)-N′-[3-(5-{5-[(4-methoxy-phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-methylphenyl]-N′-(4-methylphenyl)urea,4-Chloro-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,4-Methoxy-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl][1,1′-biphenyl]-4-carboxamide,tert-Butyl3-{5-[2,4-dioxo-5-(2-thienyl-sulfonyl)-1,3-thiazolidin-5-yl]-1-pentyn-yl}-4-methylphenylcarbamate,tert-Butyl3-(5-{5-[(3,4-dimethoxy-phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenylcarbamate,tert-Butyl3-[5-(2,4-dioxo-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidin-5-yl)-1-pentynyl]-4-methylphenylcarbamate,tert-Butyl3-[5-(2,4-dioxo-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidin-1-pentynyl]-4-methylphenylcarbamate,N-(tert-Butyl)-3-(5-{5-[(5-chloro-2-thienyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylbenzamide,N-(tert-Butyl)-3-{5-[2,4-dioxo-5-(2-thienylsulfonyl)-1,3-thiazolidin-5-yl]-1-pentynyl}-4-methylbenzamide,N-(tert-Butyl)-3-(5-{5-[(3,4-dimethoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylbenzamide,N-(tert-Butyl)-3-[5-(2,4-dioxo-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidin-5-yl)-1-pentynyl]-4-methylbenzamide,4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-3-methylbenzoicAcid,N-(4-Chlorobenzyl)-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-4-yl]propionamide,N-[2-(4-Chlorophenyl)ethyl]-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]propionamide,4-(tert-Butyl)-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(5-chloro-2-thienyl)sulfonyl]-1,3-thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)-4-pentynyl]-5-(2-thienylsulfonyl)-1,3-thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(3,4-dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidine-2,4-dione,5-[(5-Chloro-2-thienyl)sulfonyl]-5-[5-(2,5-dichlorophenyl)-4-pentynyl]-1,3-thiazolidine-2,4-dione,5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-(2-thienylsulfonyl)-1,3-thiazolidine-2,4-dione,5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-[(3,4-dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione,5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}-3-thiazolidine-2,4-dione,5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidine-2,4-dione,tert-Butyl3-(5-{5-[(5-chloro-2-thienyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenylcarbamate,5-[(4Z)-5-(4-Chloro-phenyl)pent-4-enyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,5-[(4E)-5-(4-Chlorophenyl)pent-4-enyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[3-(4-Chlorophenyl)propyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(3-Aminophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-(3-Phenylallyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,Enantiomer of(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid tert-Butyl Ester (less polar), Enantiomerof(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid tert-Butyl Ester (more polar),5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfinyl)thiazolidine-2,4-dione,Benzyl5-[5-(5-{[(benzyloxy)carbonyl]-amino}-2-methylphenyl)pent-4-ynyl]-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,4-Nitrobenzyl 5-[(4-methoxyphenyl)sulfonyl]-5-{5-[2-methyl-5-({[(4-nitro benzyl)oxy]carbonyl}amino)phenyl]pent-4-ynyl}-2,4-dioxo-1,3-thiazolidine-3-carboxylate, Methyl5-(5-{5-[(methoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,Isopropyl5-(5-{5-[(isopropoxycarbonyl)-amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,Neopentyl5-[(4-methoxyphenyl)sulfonyl]-5-[5-(2-methyl-5-{[(neopentyloxy)carbonyl]-amino}phenyl)pent-4-ynyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,Butyl5-(5-{5-[(butoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxy-phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate, Isobutyl5-(5-{5-[(isobutoxycarbonyl)-amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(3-imidazol-1-yl-propyl)-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-3-methyl-thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(2,4-diethoxybenzyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-3-(4-nitrobenzyl)thiazolidine-2,4-dione,and5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidine-3-carboxylicacid 2-methoxy ethyl ester.
 16. A pharmaceutical composition comprisingan effective amount of a compound of claim 1 in combination with one ormore pharmaceutically acceptable carriers.
 17. A pharmaceuticalcomposition according to claim 16 wherein R₆ is hydrogen, n is 3, m is2, W is

or a pharmaceutically acceptable salt thereof.
 18. A pharmaceuticalcomposition according to claim 16 wherein R₆ is hydrogen, n is 3, m is2, W is

Ar is a moiety of the formula:

or a pharmaceutically acceptable salt thereof.
 19. A pharmaceuticalcomposition according to claim 16 wherein R₆ is hydrogen, n is 3, m is2, W is

Ar is a moiety of the formula:

Ar′ is a moiety of the formula:

or a pharmaceutically acceptable salt thereof.
 20. A pharmaceuticalcomposition according to claim 16 wherein R₆ is hydrogen, n is 3, m is2, W is

Ar is a moiety of the formula:

Ar′ is thienyl or pyridinyl or a pharmaceutically acceptable saltthereof.
 21. A pharmaceutical composition according to claim 16 whereinR₆ is hydrogen, n is 3-6, m is 2, W is

or a pharmaceutically acceptable salt thereof.
 22. A pharmaceuticalcomposition according to claim 16 wherein R₆ is hydrogen, n is 3-6, m is2, W is

Ar is a moiety of the formula:

or a pharmaceutically acceptable salt thereof.
 23. A pharmaceuticalcomposition according to claim 16 wherein R₆ is hydrogen, n is 3-6, m is2, W is

Ar is a moiety of the formula:

Ar′ is a moiety of the formula:

or a pharmaceutically acceptable salt thereof.
 24. A pharmaceuticalcomposition according to claim 16 wherein R₆ is hydrogen, n is 3-6, m is2, W is

Ar is a moiety of the formula:

Ar′ is thienyl or pyridinyl or a pharmaceutically acceptable saltthereof.
 25. A pharmaceutical composition according to claim 16 whereinR₆ is hydrogen, n is 1, m is 2, W is

or a pharmaceutically acceptable salt thereof.
 26. A pharmaceuticalcomposition according to claim 16 wherein R₆ is hydrogen, n is 1, m is2, W is

Ar is a moiety of the formula:

or a pharmaceutically acceptable salt thereof.
 27. A pharmaceuticalcomposition according to claim 16 wherein R₆ is hydrogen, n is 1, m is2, W is

Ar is a moiety of the formula:

Ar′ is a moiety of the formula:

or a pharmaceutically acceptable salt thereof.
 28. A pharmaceuticalcomposition according to claim 16 wherein R₆ is hydrogen, n is 1, m is2, W is

Ar is a moiety of the formula:

Ar′ is thienyl or pyridinyl or a pharmaceutically acceptable saltthereof.
 29. A pharmaceutical composition according to claim 16 whereinm is 2, Ar is phenyl substituted in the 4-position by iodo, methoxy,trifluoromethoxy, 4-pyridyloxy; Ar′ is phenyl substituted in the2-position by chloro or methyl, and in the 5-position by amino, chloro,a carbamic acid ester, a substituted carboxamide group, or in the4-position by nitro or a carbamic acid ester; W is an acetylenic group,and n is the integer 3 or a pharmaceutically acceptable salt thereof.30. A pharmaceutical composition according to claim 16 wherein thecompound is selected from the group consisting of:5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfanyl)thiazolidine-2,4-dione,5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfanyl)thiazolidine-2,4-dione,5-[11-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxy-phenylsulfanyl)thiazolidine-2,4-dione,5-(4-Methoxyphenylsulfanyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-fluorophenylsulfanyl)thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)thiazolidine-2,4-dione,5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfonyl)thiazolidine-2,4-dione,5-[11-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxyphenylsulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)thiazolidine-2,4-dione,5-[5-(2-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(3-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(p-tolylsulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-fluorobenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(naphthalene-2-sulfonyl)thiazolidine-2,4-dione,N-(4-{5-[5-(4-Chlorophenyl)pent-4-ynyl]-2,4-dioxothiazolidine-5-sulfonyl}phenyl)acetamide,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(quinoline-8-sulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-nitrobenzenesulfonyl)thiazolidine-2,4-dione,5-(4-Benzyloxybenzenesulfonyl)-5-[5-(4-chlorophenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-(4-Butoxybenzenesulfonyl)-5-[5-(4-chlorophenyl)-pent-4-ynyl]thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(naphthalene-1-sulfonyl)thiazolidine-2,4-dione,5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4-methoxy-benzenesulfonyl)thiazolidine-2,4-dione,5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-[4-(pyridin-4-yloxy)benzenesulfonyl]thiazolidine-2,4-dione,5-[5-(2,4-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-(4-Methoxybenzenesulfonyl)-5-[5-(3-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-[5-(3-Nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiazolidine-2,4-dione,5-(4-Iodobenzenesulfonyl)-5-[5-(4-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-(4-Methoxybenzenesulfonyl)-5-[5-(4-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methyl-5-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-5-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiazolidine-2,4-dione,5-(4-Iodobenzenesulfonyl)-5-[5-(2-methyl-5-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-(5-(2-Methyl-5-nitrophenyl)-pent-4-ynyl]-5-(naphthalene-1-sulfonyl)thiazolidine-2,4-dione,5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(naphthalene-2-sulfonyl)thiazolidine-2,4-dione,5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-[4-(pyridin-4-yloxy)-benzenesulfonyl]thiazolidine-2,4-dione,5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiazolidine-2,4-dione,5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)-pent-4-ynyl]thiazolidine-2,4-dione,5-(4-Iodobenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-4-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-[5-(3-Fluoro-5-nitrophenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)thiazolidine-2,4-dione,5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxy-benzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-Bromo-2-methy-phenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-Bromo-2-methylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,(4-{5-[5-(4-Methoxybenzensulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}phenyl)carbamicAcid tert-Butyl Ester, (3-Chloro-4-{5-[5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}phenyl)carbamic Acidtert-Butyl Ester,N-tert-Butyl-3-{5-[5-(4-iodo-benzenesulfonyl)-2,4-dioxothiazol-idin-5-yl]-pent-1-ynyl}-4-methyl-benzamide,(3-{5-[5-(4-Iodobenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid tert-Butyl Ester,(4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}-3-methylphenyl)carbamicAcid tert-Butyl Ester,(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid tert-Butyl Ester,(4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-3-trifluoromethylphenyl)-carbamicAcid tert-Butyl Ester,N-tert-Butyl-3-{5-[5-(4-methoxy-benzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methyl-benzamide,5-(4-Methoxybenzenesulfonyl)-5-[5-(4-trifluoromethylphenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-(4-Methoxybenzenesulfonyl)-5-[5-(4-trifluoromethoxyphenyl)pent-4-ynyl]thiazolidine-2,4-dione,3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}-4-methylbenzoicAcid Methyl Ester,5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}benzonitrile,5-[5-(4-Methanesulfonylphenyl)-pent-4-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-3-methylbenzoicAcid Methyl Ester,5-(4-Methoxybenzenesulfonyl)-5-[5-(4-pyrrol-1-yl-phenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-(4-Iodo-benzenesulfonyl)-5-[5-(4-pyrrol-1-yl-phenyl)pent-4-ynyl]thiazolidine-2,4-dione,5-[5-(4-Pyrrol-1-ylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzenesulfonyl)thiazolidine-2,4-dione,5-(3-Methoxybenzenesulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiazolidine-2,4-dione,5-(4-Methylphenylsulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiazolidine-2,4-dione,5-(4-Methoxybenzenesulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiazolidine-2,4-dione,5-(4-Methoxybenzenesulfonyl)-5-(3-pyridin-3-ylprop-2-ynyl)thiazolidine-2,4-dione,5-(3-Thiophen-2-yl-prop-2-ynyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,5-[3-(4-Phenoxyphenyl)prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-(5-Pyridin-3-yl-pent-4-ynyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,5-[5-(5-Amino-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid Benzyl Ester,(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid 4-Nitro-Benzyl Ester,(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid 4-Chloro-phenyl Ester,(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid Methyl Ester,(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid Isopropyl Ester,(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid Neopentyl Ester,(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid Butyl Ester,(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid Isobutyl,N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2-methylpropanamide,N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-3,3-dimethylbutanamide,N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2,2-dimethylpropanamide,N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2-phenylacetamide,N-Benzyl-N′-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,N-(4-Methoxyphenyl)-N′-[3-(5-{5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,N-(4-Chlorophenyl)-N′-[3-(5-{5-[(4-methoxy-phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-methylphenyl]-N′-(4-methylphenyl)urea,4-Chloro-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,4-Methoxy-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl][1,1′-biphenyl]-4-carboxamide,4-(tert-Butyl)-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(5-chloro-2-thienyl)sulfonyl]-1,3-thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)-4-pentynyl]-5-(2-thienylsulfonyl)-1,3-thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(3,4-dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidine-2,4-dione,5-[(5-Chloro-2-thienyl)sulfonyl]-5-[5-(2,5-dichlorophenyl)-4-pentynyl]-1,3-thiazolidine-2,4-dione,5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-(2-thienylsulfonyl)-1,3-thiazolidine-2,4-dione,5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-[(3,4-dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione,5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}1,3-thiazolidine-2,4-dione,5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidine-2,4-dione,tert-Butyl3-(5-{5-[(5-chloro-2-thienyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenylcarbamate,tert-Butyl3-{5-[2,4-dioxo-5-(2-thienyl-sulfonyl)-1,3-thiazolidin-5-yl]-1-pentyn-yl}-4-methylphenylcarbamate,tert-Butyl3-(5-{5-[(3,4-dimethoxy-phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl-carbamate,tert-Butyl3-[5-(2,4-dioxo-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidin-5yl)-1-pentynyl]-4-methylphenyl-carbamate,tert-Butyl3-[5-(2,4-dioxo-5-{[5-(2-pyrid-inyl)-2-thienyl]sulfonyl}-1,3-thiazolidine-5-yl)-1-pentynyl]-4-methylphenyl-carbamate,N-(tert-Butyl)-3-(5-{5-[(5-chloro-2-thienyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylbenzamide,N-(tert-Butyl)-3-{5-[2,4-dioxo-5-(2-thienylsulfonyl)-1,3-thiazolidin-5-yl]-1-pentynyl}-4-methylbenzamide,N-(tert-Butyl)-3-(5-{5-[(3,4-dimethoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylbenzamide,N-(tert-Butyl)-3-[5-(2,4-dioxo-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidin-5-yl)-1-pentynyl]-4-methylbenzamide,4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-3-methylbenzoicAcid,N-(4-Chlorobenzyl)-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-4-yl]propionamide,N-[2-(4-Chlorophenyl)ethyl]-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]propionamide,5-[(4Z)-5-(4-Chloro-phenyl)pent-4-enyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,5-[(4E)-5-(4-Chlorophenyl)pent-4-enyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[3-(4-Chlorophenyl)propyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(3-Aminophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-(3-Phenylallyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,Enantiomer of(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid tert-Butyl Ester (less polar), Enantiomer of(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamicAcid tert-Butyl Ester (more polar),5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfinyl)-thiazolidine-2,4-dione,Benzyl5-[5-(5-{[(benzyloxy)carbonyl]-amino}-2-methylphenyl)pent-4-ynyl]-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,4-Nitrobenzyl 5-[(4-methoxyphenyl)sulfonyl]-5-{5-[2-methyl-5-({[(4-nitro benzyl)oxy]carbonyl}amino)phenyl]pent-4-ynyl}-2,4-dioxo-1,3-thiazolidine-3-carboxylate, Methyl5-(5-{5-[(methoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,Isopropyl5-(5-{5-[(isopropoxycarbonyl)-amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,Neopentyl5-[(4-methoxyphenyl)sulfonyl]-5-[5-(2-methyl-5-{[(neopentyloxy)carbonyl]-amino}phenyl)pent-4-ynyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,Butyl5-(5-{5-[(butoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxy-phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate, Isobutyl5-(5-{5-[(isobutoxycarbonyl)-amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(3-imidazol-1-yl-propyl)-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-3-methyl-thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(2,4-diethoxybenzyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-3-(4-nitrobenzyl)thiazolidine-2,4-dione,and5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidine-3-carboxylicacid 2-methoxy ethyl ester.
 31. A process for the preparation of acompound of Formula (I):

wherein: Ar is 1-naphthyl, 2-naphthyl, 8-quinolinyl, 2-thienyl,5-chloro-2-thienyl, 5-(2-pyridyl)-2-thienyl, 2-pyridinyl, substituted2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl, 2-pyrimidinyl,2-benzoxazolyl, 2-benzthiazolyl, 2-benzimidazolyl, 2-furanyl,2-benzo-[b]-furanyl, 2-benzo-[b]-thienyl or a moiety of the formula:

R₁ is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms,4-pyridyloxy, azido, nitro,acetamido, trifluoromethoxy, phenoxy, or benzyloxy; R₂ is hydrogen,fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbon atoms, alkoxy of 1to 6 carbon atoms, trifluoromethoxy, phenoxy, or benzyloxy; m is 0, 1 or2; R₆ is hydrogen; Y is 2-methoxyethyl, alkyl is 1 to 6 carbon atoms,benzyl, or substituted benzyl; W is

 E— and Z——CH═CH—, —CONH—, —CONHCH₂—, —CONHCH₂CH₂— or —CH₂—CH₂—; n is aninteger of 1 to 9; Ar′ is thienyl, pyridinyl or a moiety of the formula:

R₃, R₄, R₅, are independently selected from hydrogen, alkoxy of 1 to 6carbon atoms, alkyl of 1 to 6 carbon atoms, fluoro, bromo, chloro, iodo,nitro, amino, hydroxy, azido, cyano, phenyl, phenoxy, trifluoromethyl,trifluoromethoxy, methanesulphonyl, 1-pyrrolyl, —CO₂R₇, —CONHR₈,—CH₂CONHR₉, —NHCO₂R₁₀, —NHCOR₁₁, and —NHCONHR₁₂; R₇ is selected from H,and alkyl of 1 to 6 carbon atoms, R₈ is selected from H, and alkyl of 1to 6 carbon atoms; R₉ is selected from H, and alkyl of 1 to 6 carbonatoms; R₁₀ is selected from alkyl of 1 to 6 carbon atoms, benzyl,nitrobenzyl, and chlorophenyl; R₁₁ is selected from alkyl of 1 to 6carbon atoms, benzyl, phenyl, halophenyl, alkyl(1 to 6 carbonatoms)phenyl, alkoxy(1 to 6 carbon atoms)phenyl, and biphenyl; R₁₂ isbenzyl, alkyl of 1 to 6 carbon atoms, alkoxy(1 to 6 carbon atoms)phenyl,halophenyl, and alkyl(1 to 6 carbon atoms)phenyl; provided that when Wis

 then n is other than 2; further provided that when n is 1, m is 0 or 2,R₆ is H and W is

 then: Ar is not phenyl, 2-naphthyl, alkyl substituted phenyl, alkoxysubstituted phenyl, halogen substituted phenyl, 2-pyridinyl, substituted2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl, 2-pyrimidinyl,2-benzoxazolyl, 2-benzthiazolyl, 2-benzimidazolyl, 2-furanyl,2-benzo-[b]-furanyl, 2-thienyl, 2-benzo-[b]-thienyl; and Ar′ is notphenyl, alkyl substituted phenyl, perfluoroalkyl (mono or di)substitutedphenyl, halogen substituted phenyl, alkoxy substituted phenyl,perfluoroalkoxy substituted phenyl and alkylthio substituted phenyl; orpharmaceutically acceptable salts thereof, which comprises: reacting acompound of the formula:

with an alkyne of the formula:  Ar′W—(CH₂)_(m)—LG wherein LG is aleaving group, in the presence of a base to give a compound of Formula(I) or a pharmaceutically acceptable salt thereof.
 32. The processaccording to claim 31 wherein the base is selected from alkali metalhydrides, alkali metal alkyls and alkali metal amide bases.
 33. Theprocess according to claim 32 wherein the alkali metal hydride is sodiumhydride.
 34. The process according to claim 32 wherein the alkali metalalkyl is butyl lithium.
 35. The process according to claim 32 whereinthe alkali metal amide base is selected from lithium diisopropylamideand lithium bis(trimethylsilyl)amide.
 36. The process according to claim31 wherein the leaving group is p-toluenesulfonyloxy.